Genetic Disease Markers OLD News

Extracts from EEIN 1991-1994. Latest news is at the bottom. Provided by Eubios Ethics Institute , at http://eubios.info/index.html.

There have been conflicting reports as to whether Alzheimer's disease is genetically linked to particular genetic markers on chromosome 21. There is evidence that Alzheimer's disease can result from different genetic or nongenetic factors, St.George-Hyslop, P.H. et al. (1990) "Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder", Nature 347: 194-197. There is more than one cause of the disease, and another marker has been found on chromosome 19 (Nature 347 (1990), 124).
The progress in determining the genes involved in deafness is summarised by Reardon, W & Pembrey, M. (1990) "The genetics of deafness", Arch. Diseases in Childhood 1196-1197. Alternatives to family linkage studies are required because of the genetic heterogeneity, such as study of genes in mice. A review on the genetics of epilepsy is Gardiner, R.M. (1990) "Genes and epilepsy", J. Med. Genetics 27: 537-544).
The DNA amplification of the ZFX and ZFY genes for sex determination in humans, cattle, sheep and goats is described by Aasen E. & Medrano, J.F. (1990) Biotechnology 8: 1279-82. This can be used for preimplantation sex diagnosis. Further papers discussing the recent discovery of the gene for neurofibromatosis (SG 254) include: Ponder, B. (1990) "Neurofibromatosis gene cloned", Nature 346: 703-704; Roberts, L. (1990) "Down to the wire for the NF gene", Science 249: 236-238; Cell 63: 835-859 (3 papers). The NF gene appears to be involved in the control of the ras gene. The gene responsible for Marfan syndrome is now thought to be either on chromosome 8 or 15, and is responsible for a defect in microfibrils (JAMA 264 (1990), 1642-3; NEJM 323 (1990), 987-989).
The current screening methods for people at risk of developing autosomal dominant polycystic kidney disease is discussed by Parfrey, P.S. et al. (1990) "The diagnosis and prognosis of autosomal dominant polycystic kidney disease," NEJM 323: 1085-1090. In most people who are at 50% risk, imaging techniques are the only method of presymptomatic diagnosis, further work is needed to identify the genes, even though the majority of cases have a genetic marker that can be measured in family linkage studies. Another comparison of DNA versus enzyme based screening tests was reported for Tay Sachs disease (Triggs-Raine, B.L. et al. (1990) "Screening for carriers of Tay-Sachs disease among Ashkenazi Jews", NEJM 323: 6-12). Currently enzyme based tests are used, but the DNA-based test provides additional information on carrier status that may be useful. The sensitivity was similar, but the DNA-based test is simpler and can be performed at small centres.
A gene involved in the cancer xeroderma pigmentosum has been cloned, and it appears to be involved in DNA repair (Tanaka, K et al.(1990) Nature 348: 73-76). The cancer gene coding for p53 appears in familial cases of breast cancer, sarcoma and other cancers: Malkin, D. et al. (1990) Science 250: 1233-8; 1209. For a review of parental imprinting of genes and how sex-specific gene imprints may influence normal development and trigger diseases, see Sapienza, C. "Parental imprinting of genes", Scientific American (October 1990), 26-32.
The candidate genes for the human eye disease choroideraemia, and hereditary retinal degeneration in mice have been described (Dryja, T.P. (1990) "Deficiencies in sight with the candidate gene approach," Nature 347: 614; Cremeres F.P.M. et al. (1990) Nature 347: 674-677). The genetic involvement in coronary heart disease has been strengthened by a paper: Rosengren, A. et al. (1990) "Lipoprotein (a) and coronary heart disease: a prospective case-control study in a general population sample of middle aged men", BMJ 301: 1248-1251.
A recent study of the genetic influence upon behaviour was reported by Bouchard, T.J. et al. (1990) "Sources of human psychological differences: the Minnesota study of twins reared apart", Science 250: 223-228. This study involved over 100 twins, and concludes that about 70% of the variance in IQ was attributable to geneticfactors. On the other behavioural qualities such as personailty, social attitudes and interests the twins reared apart showed similar correlation to those raised together. This strengthens the case for the strong dependance of behaviour upon genetic factors, and has implications for what we should expect to find from the genome sequence data in the future.

The genetic links and molecular causes of cancer are reviewed by E.J.Stanbridge & P.C.Nowell (1990) "Origins of human cancer revisited", Cell 63: 867-74. There are many oncogenes known, and much focus on tumour supressor genes. The multistep nature of many cancers means that it is likely that many cancers will be found that include some genetic susceptability. Another paper on the mechanism of cancer is by D.A.Haber & D.E. Housman (1991) "Rate-limiting steps: the genetics of pediatric cancers", Cell 64: 5-8. It discusses Retinoblastoma, Wilm's Tumour, p53, and the models of cancer development. The 25th January, 1991 issue of Cell includes 9 review articles on different aspects of the molecular biology of cancer.
On p.9 of the EEIN No.1, mention was made of the link between the protein p53 and breast cancer. This is further discussed in Lancet 337 (1991), 329-31. A further study of the involvement of p53 with a cancer, Li-Fraumeni syndrome is reported in Nature 348 (1990), 681-2, 747-9. These mutations in p53 can occur 10-30 years before the development of cancer in Li-Fraumeni syndrome; however this mutation has also been found to be a late event in some other cancers. The total number, rather than the time of the mutation, may be the most important factor in determining the cancer. There have been further genetic links found which may be used for screening for breast cancer (Science 250 (1990), 1659, 1684-9, 1715-20; Lancet 337 (1991), 106). Breast cancer seems to develop in a progression that involves genetic events, and a genetic marker on chromosome 17 has been found to be associated with early-onset cases. Other work looked at a benign condition called proliferative breast disease, and found that it had familial links to breast cancer. This suggests that it is another genetic mutation that increases risk for cancer. Another analysis of genetic factors in breast cancer is by Neil Risch, in the Amer. J. Human Genetics (Feb. 1991), which suggests that inherited factors may be responsible for 5-10% of all cases of breast cancer. The other recent findings may increase the estimate.
Another inherited cancer syndrome is transmitted as an autosomal dominant trait, though 40% of the gene carriers do not have symptoms by 70 years of age, C.G.P.Mathew et al. (1991) "Presymptomatic screening for multiple endocrine neoplasia type 2A with linked DNA markers", Lancet 337: 7-11. This paper describes the screening that is being performed. Prenatal diagnosis may soon be possible, but surgery is an efficient treatment so many may not use such screening.
The gene for neurofibromatosis (or Von Recklinghausen disease) has been found to have homology with two tumour suppressor genes, and the link with other types of cancer is being investigated. The genetic mechanisms by which p53 functions as a tumor supressor are discussed in Science 250 (1990), 1576-9.

Disease Markers and New Technology
A review of the genetics of muscle diseases is by P.W. Dunne & H.F. Epstein (1991) "Molecular biology of human muscle disease" Biotechnology 9: 41-46. The search for genes responsible for Duchenne and myotonic muscular dystrophy and hypertrophic cardiomyopathy are summarised. The current state of diagnosis and the propects of gene and other new methods of therapy are discussed.
A comment on the genetic and environmental factors which contribute to multiple sclerosis is D.C. G.Skegg (1991) "Multiple sclerosis: nature or nurture?", BMJ 302: 247-8. There are both genetic factors, which also may account for why it is particularly prevalent in Caucasians, and environmental factors, which is reflected in the incresed incidence the further people live from the equator. The causes are still unknown, including suspected infectious agent(s).
A study in 1990 described an association between alcoholism and an allele of the dopamine D2 receptor gene. A recent paper by A.M.Bolos et al; (1990) JAMA 264: 3156-60, has found a lack of any association. However, similar to the first study the number of people involved in the study is relatively small. Larger studies are required to investigate any possible link, which is certainly on weaker ground after this study, but still requires further investigation. The description of behavioural diseases is an additional complication to the genetic variation that is observed. The NIH in the USA is funding a large study of alcoholism (Science 251 (1991), 163-4). There may be a genetic susceptibility to compulsive behaviours in general, which is influenced by environmental factors.
A review of genetic disease and lipoproteins is R.W.Mahley et al. (1991) "Genetic defects in lipoprotein metabolism. Elevation of atherogenic lipoproteins caused by impaired catabolism", JAMA 265 : 78-83. Several diseases have been studied which are shedding light on normal lipoprotein metabolism. The lipoprotein mutations are quite common, apo E defects occur in 1%, apo B defects occur in about 0.2%, and heterozygosity for LDL receptor abnormalities occur in about 0.2% of people, respectively. A letter on a genetic predisposition to coronary heart disease and the gene for apolipoprotein-CIII is Lancet 337(1991), 113-4.
A technical paper describing the use of blood sampling for genetic screening using the PCR is R.G.Roberts et al. (1990) "Direct diagnosis of carriers of Duchenne and Becker muscular dystrophy by amplification of lymphocyte RNA", Lancet 336: 1523-6. The RNA was first converted to DNA by the enzyme reverse transcriptase. The altered band was tested with direct ethidium staining of DNA gels, avoiding the use of radioactive probes. This technique is very simple, and could be expanded to other diseases. The particular advantage of using RNA screening for muscular dystrophy is that the DNA gene is very long and almost impossible to screen, but the changes in RNA size from the alleles with mutant genes are easy to detect. This could have much wider application to population screening than previous methods.
Recent research into the mechanism by which dystrophin is involved in Duchenne muscular dystrophy is reported in Scientific American (Jan 1991), 15-6. Another paper describing studies of mutated dystrophin genes is Cell 63 (1990),1239-48.
The Feb/March 1991 issue of the American J. Medical Genetics is devoted to the reports from a conference on x-linked mental retardation. A summary of some of the current research into finding the cause of Alzheimer's disease is in JAMA 265 (1991), 309-11. A review on inherited amyloidosis is in J.Med.Genetics 28 (1991), 73-8.
Another technical paper is by F.Barany (1991) "Genetic disease detection and DNA amplification using cloned thermostable ligase", PNAS 88: 189-193. It describes the use of the enzyme DNA ligase for the amplification of signals from oligonucleotide probes for allelic specific gene detection, which will be useful in an analogous way to the use of DNA Polymerase in the PCR.
For a review of the treatment and understanding of G6PDH deficiency see E.Beutler (1991) "Glucose-6-phosphate dehydrogenase deficiency", NEJM 324: 169-174. There have been 400 mutations described in this gene, and about 200 miliion people suffer from it worldwide. There will be increasing use of the more sensitive DNA probes for the analysis of it, but population screening is not recommended.
The mutations involved in the development of genetic disease can arise in different ways, and the tracing of the origin of mutations in families can be performed to help trace the roots. Such an approach is described by D.Rund et al. (1991) "Evolution of a genetic disease in an ethnic isolate: B-thalassemia in the Jews of Kurdistan", PNAS 88: 310-4. The origins of the mutations in this relatively inbred population with a high frequency of thalassemia, and the world's highest known allelic frequency of G6PDH, is discussed. The evidence supports the idea that malaria has been a strong selective force for these mutations.
A paper by H.Granda et al. (1991) "Cuban programme for prevention of sickle cell disease", Lancet 337 (Jan 19), 152-3, describes a major screening program that has reduced the number of children expected to be born suffering from sickle cell disease in Cuba by about 30%.

A product review is M.L.Riordan & J.C.Martin (1991) "Oligonucleotide-based therapeutics", Nature 350: 442-3. A general review is D.M.Danks (1991) "DNA diagnostic tests: expanding role and evolving techniques", Medical J. Australia 154: 3-7. The use and development of reliable recombinant DNA assays is discussed in Biotechnology 9 (1991), 200. A general historical paper is by M.A.Ferguson-Smith (1991) "Putting the genetics back into cytogenetics", AJHG 48: 179-82. The results of a two year program for DNA screening for Duchenne and Becker muscular dystrophy are in Medical J. Australia 154 (1991), 14-8.
A review on the use of PCR for DNA analysis which can be used for genetic screening is N. Arnheim et al. (1990) "PCR analysis of DNA sequences in single cells: single sperm gene mapping and genetic disease diagnosis", Genomics 8: 415-9. It also discusses the use of the technique for genetic mapping. Also on general uses of the PCR see Laboratory Practice 40 (3) (1991), 11-15.
A study based on records in British Columbia, Canada, has found that the general incidence of unknown birth defects does not increase with maternal age; P.A.Baird et al. (1991) "Maternal age and birth defects: a population study", Lancet 337: 527-30. Other papers on this topic are in NEJM 323 (1990), 414-5, & Vol. 324: 700-1. A review of interest is A.C.Chandley (1991) "On the parental origin of de novo mutation in man", J. Medical Genetics 28: 217-23.
John Radcliffe Hospital in Oxford, U.K., has found several cases of birth damage from the use of CVS before 10 weeks fetal life; Lancet 337 (1991), 762-3. The figures were 5 major limb abnormalities out of 289 pregnancies using CVS at 56-66 days gestation. However, reviews of 50,000 CVS procedures in the USA show no link to damage; NS (23 March 1991), 7. It may be that the very early use of CVS is more risky than thought, but other groups have not found a signifcant risk of malformation after the procedure.
A special issue of Clinics in Perinatalogy (Dec. 1990), Vol 17 (4), 749-940 focuses on fetal clinical genetics. There are a series of interesting papers, with attention both on the ethics and practice, and the scientific and medical developments. There are papers on genetic counseling, prenatal diagnosis of metabolic disease, cystic fibrosis, collagen defects in connective tissue, hemoglobinpathies, neuro-fibromatoses, Duchenne and Becker muscular dystrophy, chromosomal mosaicism in CVS, common diseases of adulthood and fetal echocardiography. This issue is useful for all those with interest in genetic counseling.
The association between p53 and familial cancer has been shown in families from different countries and geentic origins. The mutations appear to be in the same codon in China and South Africa, suggesting a hotspot of mutation because they should have had different links; Nature 350: 377-8, 427-431. Other links to cancer genes are discussed in Nature 350 (1991), 190. Another cancer related gene is described by K.W. Kinzler et al. (1991) "Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers", Science 251: 1366-70, 1317. It appears to be a suppressor gene involved in the early stages of colon cancer development.
Several papers on different diseases with genetic links that may be screened are: J.A.Naylor et al. (1991) "Detection of three novel mutations in two haemophilia A patients by rapid screening of whole essential region of factor VIII gene", Lancet 337: 635-9; the recognition of thyroid disease in the fetus, NEJM 324 (1991), 559-61; the sensitivity of ultrasound in detecting spina bifida, NEJM 324: 769-72; the mechanism of diabetic hyperglycemia and glucose transport and genetic causes, Science 251 (1991), 1200-6; the molecular basis and mutations that cause galactosemia, PNAS 88 (1991), 2633-7.
There has been a study which suggests that an altered gene for amyloid precursor protein may be acting as an autosomal dominant allele for early onset Alzheimer's disease; A.Goate et al. (1991) "Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease", Nature 349: 704-6; Nature 349: 653-4;NS (23 Feb 1991), 17; Lancet 337 (1991), 546; Science 251 (1991), 876-7; BMJ 302 (1991), 610. Only about 1-5% of Alzheimer's disease runs in families, but it is an important step in determing the cause, it is also of relevance to the cause of Down's syndrome dementia. Laboratory studies of the mutation in animals are commencing to investigate the affect and whether such animals develop Alzheimer's lesions.
A section of a gene that has been found to have direct affects on behaviour, insect song rhythm, is described in D.A. Wheeler et al. (1991) "Molecular transfer of a species-specific behavior from Drosophila simulans to Drosophila melanogaster ", Science 251: 1082-5.
The abnormality Fragile-X is the second most common major genetically-linked mental retardation, and the involvement of DNA methylation in this disease is suggested by recent papers; Cell 64 (1991), 861-6; Nature 349 (1991), 624-6, 742-3. Also of interest is R.M.Ridley et al. (1991) "Patterns of inheritance of the symptoms of Huntington's disease suggestive of an effect of genomic imprinting", J. Medical Genetics 28: 224-31. A general review of related interest is B.Charlesworth (1991) "The evolution of sex chromosomes", Science 251: 1030-33. News on the role of a newly cloned growth factor, brain-derived neurotrophic factor, involved in Parkinson's Disease is in Nature 350 (1991), 195. A review on other neural diseases is A.E.Harding (1991) "Neurological disease and mitochondrial genes", TINS 14: 132-8. A comment on schizophrenia and its genes is in JAMA 265 (1991), 1503,7.
Over the last decade there have been several reports in the USA that associate blood pressure with skin colour, claiming that blacks have higher blood pressure because of a genetic element. However, there have been other studies which link blood pressure not to colour but to socioeconomic class, which is a more environmentally dependent link, and this was confirmed by the results of a major recent study; M.J.Klag et al. (1991) "The association of skin color with blood pressure in US blacks with low socioeconomic status", JAMA 265: 599-602, comment by R.F.Murray p.639-40. There may still be some genetic alleles disproportionately distributed among blacks and whites. Another possible racial difference is reported in the way that people respond to early HIV intervention, suggesting that blacks may have adverse effects of such intervention using the current procedures; JAMA 265 (1991), 1065-6. It calls for more study of this. Another paper indicating racial differences in metabolism is M.F. Saad et al. (1991) "Racial differences in the relation between blood pressure and insulin resistance", NEJM 324: 733-9. Of much more probable environmental causes is the lowering life expectancy of US blacks reported in Scientific American (March 1991), 15-6. In Australia there is an increase in death rate among young aborigines, and the general life expectancy is 12 to 15 years less than Caucasians; BMJ 302 (1991), 551-2.

On the subject of breast cancer genetics see Lancet 337: 1039; BMJ 302: 861-2. On breast cancer screening, see BMJ 302: 845, and on melanoma screening see MJA 154: 338-43. A letter regarding p53 and liver cancer is in Lancet 337: 908; and linking p53 and bladder cancers, and the detection of the change by urine samples is a paper in Science 252: 706-9; NS (11 May 1991), 22. A review on p53 is A.J.Levine et al., "The p53 tumour suppressor gene", Nature 351: 453-6. Also on p53 studies see Cell 65: 765-74. A third tumor suppressor gene, one linked to colon cancer is described in Nature 351: 188-90; Science 251: 1366-70, see also Science 252: 1067. The ras oncogene has also been linked to a rare heart disease, long QT syndrome, Science 252: 647, 704-6.
A short review on the research on hemoglobin switching is in Science 252: 383. Recent approaches to the treatment of sickle cell anemia are discussed in JAMA 265: 2097-2111. Discussing neuro-fibromatosis is NEJM 324: 1283-5.
Phenylketonuria mutations in Southern Europe are the subject of a letter in Lancet 337: 865, and comments on PKU are in Lancet 337: 1256-7. See also Y.Okano et al., "Molecular basis of phenotypic heterogeneity in phenylketonuria", NEJM 324: 1232-8. It attempts to relate the 10 known disease-causing alleles of phenylalanine hydroxylase with the phenotypic severity, and suggests that the establishment of the genotype can aid the management of the disease.
A gene that appears to be responsible for Fragile X syndrome is described in several reports; Science 252: 1070, 1097-1102, 1179-81; Cell 65: 905-14; Nature 351: 439-40. Several groups have discovered the gene site simultaneously, and found that the genetic mutation itself is very mutable unlike exisitng ideas about genetic mutations and disease. The method of transmission of the gene defect is now under close scrutiny.
A proposed mechanism by which the mutation in amyloid beta precursor protein can lead to Alzheimer's disease is in Nature 350: 564. Also see TINS 14: 218-9; Lancet 337: 1342-3. Comments on improving the methods, including the recommended use of marker hormones for the prenatal screening of Down's syndrome are in BMJ 302: 965, 1133-6, 1207, 1275; JAMA 265: 1797-8.
Papers on Huntington's Disease include: M.I.Skraastad et al., "Presymptomatic, prenatal, and exclusion testing for Huntington Disease using seven closely linked DNA markers", AJMG 38: 217-22, which describes a programme among 23 families in the Netherlands. F.Ajimar et al., "Genetic analysis of Huntington Disease in Italy", AJMG 39: 211-4. A genetic marker for familial amyotrophic lateral sclerosis has been found on chromosome 21; NEJM 324: 1381-4, 1430-2.
The relationship between dietary cholesterol and serum cholesterol level is discussed in NEJM 324: 912-3. The effects of coffee on cholesterol level are discussed in BMJ 302: 804. There is a substance that is removed by filtering the coffee. A general paper from the AMA Board of Trustees is "Drug abuse in the United States: Strategies for Prevention", JAMA 265: 2102-7. In this paper the case for the genetic link for alcoholism is presented, but most of the other factors discussed are environmental, as are the strategies for prevention.
A study reported in the NEJM 324: 998, of the deaths of people in Southern California, found that left-handed people died an average of 9 years earlier than right-handed. This is discussed in Nature 350: 545. When cases were sex divided the average longevity for left-handed verus right-handers for males was 72 versus 62, and females 78 versus 73, respectively. Previous studies have found that left-handers are more suspectable to autoimmune disorders, and are more likely to have been born prematurely. They might have a higher accident rate, in the right-handed environment. However this data may not be statistically meaningful because they did not look at the age structure and population relationships of left and right handers in the population; NS (27 April 1991), 11; Science 252: 916.
On the issue of age expectancy itself, see the search for aging genes described in SA (April 1991), 10; and a book reviews inNature 351: 198 and Science 252: 1000-1. Letters on IQ and heredity appear in Science 252: 191-2. The olfactory receptor gene, the receptor that allows us to smell, has had its gene cloned: Cell 65: 175-187;Science 252: 209-10; Nature 351: 275-6.
Short reviews on the methods and detection of congenital abnormalities are in BMJ 302: 949-50, 1013-6. They include brief discussion of the counseling and ethical questions, such as the advantages of offering diagnostic services to those who do not want abortions. By the same author, G. Chamberlain, are reviews on checks for fetal wellbeing, BMJ 302: 837-9, 900-2; on vaginal bleeding in early pregnancy, p. 1141-3, 1195-7; and on medical problems in pregnancy, p. 1262-6, 1327-30. Another general paper is J.D.Hamerton, "Prenatal diagnosis - The medical genetics perspective", CMAJ 144: 1129-32. On detection of ectopic pregnancies see BMJ 302: 1308-11, and on sonography see JAMA 265: 2851-5.
In EEIN 1: 38, several cases of race-related differences in mortality were reported. The question of the high aboriginal mortality rate is discussed in two papers in MJA 154: 235-9, 419-22. The high suicide rate is also discussed, in what is called the fourth world. The health care of "hispanics" is discussed in JAMA 265: 2064-6. See also BMJ 302: 802-3 for health education and minorities. On Canadian indian's health see Lancet 337: 841.
On the general influence of maternal factors see Lancet 337: 1288, and BMJ 302: 1178-80. On genetic diagnosis of mitochondrial encephalopathies see Lancet 337: 1311-3.
Letters on the association of the dopamine receptor and alcoholism appear in JAMA 265: 2667-8.
A genetic program may be involved in bird migration. Scientific evidence for this comes from studies of European blackcaps; Behavioural Ecology & Sociobiology 28: 9; NS (20 April 1991), 15.

Two genes associated with insulin dependent diabetes have been identified; J.A. Todd et al., "Genetic analysis of autoimmune type I diabetes mellitus in mice", Nature 351: 542-7; 519-20; BMJ 302: 1423; Lancet 337: 1538. The gene is not associated with the HLA genes.
The defect behind Marfan syndrome has been identified; Nature 352: 279-81. Three papers in the 25th July issue of Nature describe the genes involved; Nature 352: B. Lee et al., p.330-4, C.L. Maslen et al., p. 334-7, H.C. Dietz et al., p. 337-9. Mutations in fibrillin genes are responsible.
As reported the gene for Fragile X-syndrome has been identified; EEIN 1: 51, BMJ 302: 1359. A screening procedure for that syndrome is in AJHG 48: 1051-7, it will be able to be improved using the new knowledge. A genetic predisposition to iatrogenic Creutzfeldt-Jakob disease is reported in Lancet 337: 1441-2; see also Nature 352: 340-2. In Greig syndrome, a gene mutation in a zinc finger is involved see Nature 352: 539-40. See also; Y. Ma et al., "A mutation in the human lipoprotein lipase gene as the most common cause of familial chylomicronemia in French Canadians", NEJM 324: 1761-6. It also describes a dot blot test procedure.
Studies on the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein continue. By altering lysine 95 and 335 the anion selectivity of CFTR can be changed; M.P. Anderson et al., "Demonstration that CFTR is a Cl channel by alteration of its anion selectivity", Science 253: 202-5. If the R domain is deleted, the protein conducts Cl independently of cAMP; D.P. Rich et al., "Effect of deleting the R Domain on CFTR generated Cl channels", Science 253: 205-9. See also Nature 352: 194-5. There were indications that not only a Cl channel is involved, but a study by J. Barasch et al., "Defective acidification of intracellular organelles in cystic fibrosis", Nature 352: 70-3; 23-4; is also consistent with the protein being a Cl channel. Acidification of intracellular compartments is observed, due to the lack of function of the Cl pump, while the proton pump is still functioning. A somewhat contrary paper is C.L. Ward et al., "Cystic fibrosis gene expression is not correlated with rectifying Cl channels", PNAS 88: 5277-81.
Comment on the improvement of our genetic understanding of common diseases, especially cancer, is in BMJ 302: 1486-7; Lancet 337: 1538; JAMA 265: 3132-4. A review is M. Hollstein et al., "p53 mutations in human cancers", Science 253: 49-53. See other papers on p53 in PNAS 88: 4976-80 and 5413-7; Nature 352: 345-7. On retinoblastoma and the involvement of myc proteins see Nature 352: 189-90, 541-4. On the spontaneous mutation rate in the intestine see Nature 352: 200-1.
Another new genetic finding is reported by I. Henry et al., "Uniparental paternal disomy in a genetic cancer-predisposing syndrome", Nature 351: 665-7, also p. 667-90, 609-10. This is a fetal overgrowth syndrome, and it mat be another case of parental imprinting of genes, see also Science 252: 1250-1. A report on our understanding of the cell cycle is in Science 252: 1490-2.

A pattern of mutations in the p53 gene in patients with hepatocellular carcinoma is described in Nature 352: 764. The p53 gene has been found to be mutated in a patient with intercranial ependymona; PNAS 88: 7825-9. p53 mutations appear to be a general susceptibility mutation to developing malignant growths. An international registry of p53 mutations is being set up, see Lancet 338: 813. On screening for p53 see PNAS 88: 8405-9; and on association of the glutathione S-transferase mu locus with squamous carcinoma of the lung see Carcinogenesis 12: 1533-7. See also C.N. Ellis et al., "Prognostic applications of DNA analysis in solid malignant lesions of humans", Surgery: Obstetrics & Gynecology 137: 329-42. Mutations in the human retino-blastoma gene are described in Nature 353: 83-6. For mutations connected to Wilm's tumour see Nature 353: 431-4. On an immunologic (the antigen HLA-DQw3) susceptibility to cervical carcinoma see Nature 352: 723-5. On developmental genetics and childhood cancer see a conference report in Cancer Research 51: 5435-9.
Genetic mapping of loci that code for blood pressure regulating factors in rats are described in P.Hilbert et al., "Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats", Nature 353: 521-9, see also p. 499 for comment. These also describe the use of two rat strains as models of human hypertension.
A susceptibility locus for the mouse equivalent of insulin-dependent diabetes is described in Nature 353: 260-2, 262-5. Different stages in the progression of diabetes may be controlled by different genes. A gene bank for diabetes research has been setup; NS (31 Aug 1991), 10. Also on diabetes see AJHG 49: 42-8.
On the genetics of deafness see NS (19 Oct 1991), 12. Developmental dyslexia appears to be a heterogeneous, but nevertheless, genetic disease; JAMA 266: 1527-34. On Fragile X syndrome see Lancet 338: 956-8; PNAS 88: 8302-6.
A review on Duchenne's muscular dystrophy is in Amer. J. Medical Sciences 302: 118-23; on an in utero muscle biopsy see Amer. J. Obstetrics & Gynecology 165: 728-32. On Alzheimer's patient's protein mutations see AJHG 49: 511-7. On Alzheimer's see SA (Nov 1991), 40-7. See also R.E.Tanzi, "Gene mutations in inherited amyloidopathies of the nervous system", AJHG 49: 507-10, see also p.518-21, 522-8.
It appears that in Hemophilia A only half the cases are due to factor VIII deficiency; JAMA 266: 1612-3. On the mutations responsible for Factor XI deficiency in Ashkenazi Jews see a review in NEJM 325: 153-8.
Book reviews on general books on genetic diseases are in AJHG 49: 694-5; Archives of Diseases in Childhood 66: 1005. On hereditary unstable DNA see Lancet 338: 289-92. On imprinting and diseases see Lancet 338: 413-4. On mitochondrial DNA mutations and disease see JAMA 266: 1739-40, 1812-6; MJA 154: 646-7. DNA analysis has been used to diagnose tuberculosis; Lancet 338: 364-6.

On the prospects for a cure for cystic fibrosis (CF) see NS (7 Dec 1991), 30-34. The CFTR protein has been localised to apical regions of epithelial cells, PNAS 88: 9262-6. See also TIBS 16: 474-7; J. Medical Genetics 28: 807; NEJM 325: 1630-4.
On cancer genes see reviews in the 22 November issue of Science, including; R.A. Weinberg, "Tumor suppressor genes", Science 254: 1138-46; S.A. Aaronson, "Growth factors and cancer", Science 254: 1146-53; E. Solomon et al., "Chromosome aberrations and cancer", Science 254: 1153-60. A new tumor suppressor gene has been identified on chromosome 21; Science 253: 661-5, 665-9; Cell 66: 589-600, 601-613; Nature 353: 696-8; Lancet 338: 1363-4. Environmentally induced mutations in the p53 gene are described in Lancet 338: 1356-59 (from aflatoxins); PNAS 88: 10124-8 (UV-light). The origin of acute leukemias is discussed in Cell 67: 641-4, and gene mapping in cancer is reviewed in Cancer Genetics & Cytogenetics 55: 139-47.
The mutation of DNA is discussed in Nature 354: 114-6, particularly the neutral mutation hypothesis test applied to alcohol dehydrogenase gene. Also see E.C. Gadow et al., "Chromosome rearrangements among couples with pregnancy losses and other adverse reproductive outcomes", AJMG 41: 279-81. The theory of genetic load is discussed in a book review in Science 354: 1049; Nature 354: 119. See also Nature 354: 324, 326-7. Recent research suggests that neuronal human cells may have DNA which recombines, as the immunoglobulin family genes do, our DNA is more fluid than we think and it might even be fluid when we do think, and remember.
A report from a recent conference on schizophrenia is Nature 353: 693-4. A report from a conference on depression is Science 254: 1450-2. A book review of Peter McGuffin & Robin Murray, eds., The New Genetics of Mental Illness (Oxford: Butterworth Neinemann 1991, 304pp, 35) is in Lancet 338: 1065. Other book reviews are of D.J. Weatherhall, ed., The New Genetics and Clinical Practice , 3rd ed., (Oxford University Press 1991, 376pp., 15), in Lancet 338: 1445; and P.R. McGugh & V.A. McKusick, eds., Genes, Brain, and Behavior (New York: Raven Press 1991, Association for Research in Nervous and Mental Disease, Vol 69, 237pp., US$99) in NEJM 325: 1111. A new X-linked form of mental retardation that is associated with -thalassemia is reported in 4 papers in J. Medical Genetics 28: 729--45.
A gene mutation associated with early-onset Alzheimer's disease is reported in M.-C. Chartier-Harlin et al., "Early-onset Alzheimer's disease caused by mutations at codon 717 of the ß-amyloid precursor protein gene", Nature 353: 844-6. See also TIPS 12: 383-8; BMJ 303: 1215-6.
Several other papers related to other genetic diseases include; neurofibromatosis; Nature 353: 864-6; D.H. Gutmann et al., "Identification of the neurofibromatosis type 1 gene product", PNAS 88: 9658-62; skin blister diseases; Science 254: 1111-2; Marfan's syndrome; BMJ 303: 1414-5; on giantism; Lancet 338: 1454-5; Gaucher's disease; NEJM 325: 1354-60; diabetes; Nature 354: 155-9, 238-41; and on retinitis pigmentosa; Nature 354: 478-80, 480-3. The DNA-binding properties of testis-determining gene are described in Nature 354: 317-20; also see Nature 354: 483-6, 486-9. Research on aging is discussed in Science 254: 936-8, 1597; Biotechnology 9: 822-3.
A paper discussing why pigmies in different areas of the world may be so small is; Annals Human Biology 18: 113-120; Nature 354: 111-2.

There are 3 papers on the mapping of the mutations in the myotonic dystrophy gene in Nature 355: 545-51. It appears that the mutations in the dystrophin gene that are the cause for muscular dystrophy get larger each generation, making the severity of the disease greater each generation. Similar phenomenon appear to occur for Fragile X syndrome and X-linked spinal & bulbar atrophy; New York Times (6 Jan 1991), A1, B8. This adds another issue to the question of genetic counseling, and a further factor to be considered by parents who suffer from mild forms of this disease.
On diagnostic of polycystic kidney disease see P.C. Harris et al., "Rapid genetic analysis of families with polycystic kidney disease 1 by means of a microsatellite marker", Lancet 338 (1991), 1484-7. Analysis can be completed using non-radiative labelling methods within 8 hours.
A call for population screening of Jews for Gaucher disease is based on the paper; E. Beutler et al., "Identification of the second common Jewish Gaucher disease mutation makes possible population-based screening for the heterogeneous state", PNAS 88 (1991), 10544-7. The two known mutations accounted for 95% of the mutations in the Jewish population studied.
On thalassemia see; T.-M. Ko et al., "Carrier detection and prenatal diagnosis of alpha-thalassemia of Southeast Asian deletion by polymerase chain reaction", Human Genetics 88: 245-8. The technique may be useful for rapid prenatal diagnosis. On thalassemia screening in Sicily; Lancet 339: 179-80. The alpha-thalassemia/mental retardation syndrome has been linked to the X-chromosome; Lancet 338: 1562-3.
A series of papers on Fragile X-syndrome are in JMG 28 (1991), 809-39. The identification of the gene will allow screening. On the method of inheritance, which is neither recessive or dominant, but follows an unusual pattern; NEJM 325: 1736-8. On direct diagnosis methods which can be used for prenatal diagnosis and counseling in addition to diagnosis of the condition in people that suffer from mental retardation, see; F. Rousseau et al., "Direct diagnosis by DNA analysis of the Fragile X syndrome of mental retardation", NEJM 325 (1991), 1673-81. See also NEJM 325 (1991), 1720-2.
On germline mutations in p53 in Li-Fraumeni syndrome see; Lancet 338 (1991), 1490-1. On prenatal diagnosis of sporadic neurofibromatosis 1; Lancet 339: 119-20. On unsuccessful screening (non-genetic) for colorectal cancer see NEJM 326: 134-5. As for all types of screening, on can ask whether it is worth doing if it does not help the patient. On the brighter side, of the development of better methods for screening and treating breast cancer see Science 254: 1719-20. On a genetic change in breast cancer; I. Bieche et al., "Loss of heterozygosity on chromosome 7q and aggressive primary breast cancer", Lancet 339: 139-43. A patient's view of breast cancer therapy trials, with a look at how informed consent can be obtained, is in Lancet 339: 44-5; also see JAMA 266 (1991), 3429-32.
A link to diabetes is reported in D. Faustman et al., "Linkage of faulty major histocompatibility complex class I to autoimmune diabetes", Science 254 (1991), 1756-61. This was detected in mouse models and confirmed in human patients. It is suggested that the lack of surface MHC class I protein may cause a defect in antigen presentation which impairs the development of self tolerance which could result in autoimmune disease.
A possible gene involving in iron overload is suggested by studies reported in V. Gordeuk et al., "Iron overload in Africa. Interaction between a gene and dietary iron content", NEJM 326: 95-100, 126-7. On genetics and human nutrition see a book review in AJHG 49: 1385-6.
A review is J.W. MacCluer & C.M. Kammerer, "Dissecting the genetic contribution to coronary heart disease", AJHG 49 (1991), 1139-44. A mutation that causes hypertension in humans and animals has been identified; R.P. Lifton et al., "A chimaeric 11b-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteroism and human hypertension", Nature 355: 262-5. A gene linked to the hardening of arteries has been identified; NS (8 Feb 1991), 21. See also; A. Rosenzweig et al., "Preclinical diagnosis of familial hypertrophic cardiomyopathy by genetic analysis of blood lymphocytes", NEJM 325: 1753-60.
On a human transposon, which was detected in some hemophilia A patients, see; Science 254 (1991) 1728-9; 1805; Lancet 339: 215-6. This transposon is called LINE, and will be useful to study how they work in altering the genome. Recently there were also discoveries that another common human genetic repeat element, Alu sequences, were associated with some human genetic diseases.

The instability of myotonic muscular dystrophy and several other genetic diseases has recently been discovered; EEIN 2: 23; Cell 68: 799-808; Science 255: 801, 1253-5, 1256-8. Further discussion of this is in Nature 356: 15; Lancet 339: 358, 692, and on paternal inheritance of Duchenne dystrophy (DMD); AJMG 42: 213. A method to treat DMD using myoblast transplantation is described in I. Gussoni et al., "Normal dystrophin transcripts detected in Duchenne muscular dystrophy patients after myoblast transplantation", Nature 356: 435-8. For biochemical analysis of dystrophin; Nature 355: 696-702.
The clinical implications of genomic imprinting are discussed in NEJM 326: 827-9. Other diseases with genetic links identified recently include; Marfan's syndrome, NEJM 326: 905-9, JMG 29: 73-4; diabetes, Nature 356: 162-4; fatal familial insominia, NEJM 326: 444-9; malignant hyperthermia, BMJ 304: 791-2; von Hippel-Lindau disease, JAMA 267: 1226-31; keratin gene mutations, BMJ 304: 590; C2 deficiency, NEJM 326: 871-4. Fibrinogen alleles are associated with different risks of peripheral atherosclerosis; Lancet 339: 693-6.
More cancer research has found association with cancer and p53 and ras genes, and how these genes may be mutated in people exposed to radon; K.H. Vahakangas et al., "Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners", Lancet 339: 576-80. Mutations and overexpression of p53 in head and neck cancer may be linked to heavy smoking and drinking; Lancet 339: 502-3, see also Science 255: 459-62; Nature 356: 215-21. Another gene has been found in animals which gives a 70 fold increased susceptibility to renal cell carcinoma; Science 255: 1693-5. The relationship between viruses and major histocompatibility antigenes and cancer is discussed in Nature 356: 17-8, 22,23, 66-8
A linkage marker to familial adenomatous polyposis is described in F. MacDonald et al., "Predictive diagnosis of familial adenomatous polyposis with linked DNA markers: population based study", BMJ 304: 869-72, 858-9.

The myotonic dystrophy gene was located very soon after the mapping of the locus, as described in EEIN 2: 23, 38. It has been claimed as one of the early finds of the human genome project; HGN (March 1991), PNAS 89: 2331-5; Lancet 339: 1125-8. The role of this and other triplet repeat mutations in human disease is discussed in Science 256: 784-9. The diagnosis of muscular dystrophy by PCR is reported in JAMA 267: 2609-15.
A review of the molecular genetics of cancer is in BMJ 304: 1234-6. A suspect gene , BRCA1 on chromosome 17 is implicated in breast cancer, and it is said that this gene may cause breast or ovarian cancer by age 50 in about 1 of 170 women; HGN (March 1991), 3-4. Genetic counseling can be performed for some cancers, Lancet 339: 1181. The role of p53 in cancer is discussed in NS (16 May 1992), 14; NEJM 326: 1301-8, 1309-15, 1350-2; Science 256: 827-30; Lancet 339: 1070-3, 1330-1, and the mechanism of skin cancer in NS (16 May 1992), 23-8. Identification of the ras oncogene can be made in faeces of patients with curable colorectal tumours; Science 256: 32, 102-5; Lancet 339: 1141-2. On the APC gene and adenomatous polyposis see Science 256: 668-70; and on somatic mutations in neurofibromatosis, Cell 69: 265-73, 275-81; Nature 356: 713-5. On malignant hyperthermia see Science 256: 789-94. A link between mammography and breast cancer deaths is discussed in Science 256: 1128-9. The incidence of prostrate cancer may be related to reduced activity of 5-alpha-reductase; Lancet 339: 887-9.
Genes related to Parkinson's disease are discussed in Science 256: 1390. Studies on genetic links to psychiatric behaviours, depression and phobias, are in Archives of General Psychiatry 49: 257-281; see also Nature 356: 670. The genetics of drug dependence can be studied using animal models; TIPS 13: 212-7. Relating to Fragile X syndrome, on New York's screening program see AJMG 43: 328-32; on in Spain, AJMG 43: 333-8; and on population screening in Australia, Lancet 339: 1210-3, and a special issue of AJMG (April 15/ May 1) 43.
On Alzheimer's disease see Science 256: 184-5; 780-3; Parkinson's disease, Lancet 339: 1017-8; and Huntington's gene see Nature Genetics 1: 99-108, and on the age at onset and life table risks for genetic counseling see JMG 29: 239-42. Genes relating to obesity are discussed in Cell 69: 217-20; hypertension, Lancet 339: 1142-3, and diabetes, Nature 356: 721-3; Lancet 339: 1047, 1307-10. On cystic fibrosis see Science 256: 444-5; 774-9; on single cell analysis Lancet 339: 1190-2; on Gaucher's disease, Science 256: 794-9; and on polycystic kidney disease, Lancet 339: 1146-9.
On the role of mitochondrial DNA in genetic disease and aging see Science 256: 628-32. Programmed cell death can be protected in nematodes by the action of a single gene; Nature 356: 494-9.

A review of recent events in medical genetics and gene mapping is in JAMA 268: 368-9; ASHG 51: 231-4. A book review on human abnormalities is in Nature 358: 461-2 A diagnostic test for susceptibility to rheumatiod arthritis has been developed by the NIH; GEN 12(10),10, 19. The genes are involved in immune response, and make people under stress more susceptible to develop arthritis.
Some of the current research goals of behavioural genetics are reviewed in Science 257: 164-5, reviewing a conference held in Berlin in May. Many genetic studies are underway, and we will have to face much revelation about genes disposing us to particular behaviours in the close future. The serotonin receptor gene has been cloned; GEN 12(10), 20. It is associated with hypertension, depression, and suicide, and we can expect much more study on its effects. Another gene associated with psychological traits is the dopamine receptor and there appear to be multiple variants in the population; H.H.M. Van Tol et al., "Multiple dopamine D4 receptor variants in the human population", Nature 358: 149-2; 109. The risks of Alcoholic families to children are the topic of a book review in Nature 358: 549. The risks of living in a city include increased chance of schizophrenia; G. Lewis et al., "Schizophrenia and city life", Lancet 340: 137-40. Studies on compulsive behaviour in dogs are reported in Science 257: 480.
A book review of Alzheimer's Disease Research: Ethical and Legal Issues is in NEJM 327: 60-1. A possible risk test for Alzheimer's based on protein examination has been suggested; SA (Aug 1992), 99; NS (18 July 1992), 19. On Kallmann's syndrome; NEJM 326: 1752-5; on the frequency of uniparental disomy in Prader-Willi syndrome; NEJM 326: 1599-607; NS (1 Aug 1992), 17; on Mediterranean fever; NEJM 326: 1509-13; on Fragile X; JMG 29: 518; and on when to begin screening for Fragile X; BMJ 305: 208. A relationship between fragile sites and spontaneous abortions is proposed in Genetic Counseling 2: 205-10.
Papers on the p53 gene and cancers include Nature 358: 15-16, 80-3, 83-6; Lancet 340: 140-2, 259-63; PNAS 89: 6413-7. The inactivation of its tumour suppressor activity is almost universally involved in the development of cancers. A protein that its binds has been found. The human germinal mutation rate has been calculated to be 7.2 x 10-8 per locus; PNAS 89: 7036-40. Population data from Italy suggests that there is dominant transmission of a colorectal susceptibility gene; JMG 29: 531-8; Lancet 340: 210-1. See a letter on limiting mutagenic events in carriers of hereditary cancer susceptibility genes in AJHG 50: 1350-1. Related to calculating cancer risk is S. Lipkowitz et al., "Interlocus V-J recombination measures genomic instability in agriculture workers at risk for lymphoid malignancies", PNAS 89: 5301-5. Immunogenic antigens have been found to be associated with survival of lung cancer; NEJM 357: 14-8.
Genetic susceptibility to Schistosome infection is debated in AJHG 51: 206-8. On malaria see L. Abel et al., "Segregation analysis detects a major gene controlling blood infection levels in human malaria", AJHG 50: 1308-17. They found that about 21% of the population is predisposed to high levels of infection.
Reviews related to cardiac disease are A.M. Scanu, "Lipoprotein(a) A genetic risk factor for premature coronary heart disease", JAMA 267: 3326-9; R.M. Lawin, "Lipoprotein(a) in heart disease", SA (June 1992), 26-32. Also see R.D. Gordon et al., "Primary aldosteronism: hypertension with a genetic basis", Lancet 340: 159-61, 377-8; MJA 156: 594-6. On social and economic factors associated with heart disease patients see letters in JAMA 268: 195-7. A letter on an association between fibrinogen genes and peripheral arterial disease is in Lancet 340: 63. The environmental factors related to coronary heart disease are investigated in N. Li et al., "Electrocardiographic abnormalities and associated factors in Chinese living in Beijing and Mauritius", BMJ 304: 1596-601.
The results of a trial CF screening in Edinburgh are in M.E. Mennie et al., "Prenatal screening for cystic fibrosis", Lancet 340: 214-6; E.K. Watson et al., "Psychological and social consequences of community carrier screening programmes for cystic fibrosis", Lancet 340: 217-20; pp. 209-10. It provides a useful study on how to undergo population testing, involving 4348 women attending antenatal clinics. 14% declined to join the testing, which used a mouthwash to take samples, followed by testing of the male partners in cases were carrier status was detected. The psychological results were encouraging. The frequency of some cystic fibrosis mutations among population groups is reported in AJHG 50: 1185-94; and how the mutations affect pancreatic function; AJHG 50: 1178-84. Letters on population screening for CF include Lancet 339: 1539-40. The intermediate results of heart-lung transplantation for CF are encouraging but there is shortage of organs; Lancet 339: 1583-7.
Papers on the number of trinucleotide repeats in the myotonic dystrophy gene, and cases of DMD mutation expansion are reported in Nature Genetics 1: 192-5, and the relationship to murine gene sequence in p. 261-6. See letters in AJHG 50: 1340-2, Lancet 340: 237-9; and paper on anticipation in AJHG 51: 10-16. The cause of facioscapulohumeral muscular dystrophy has been reported from British researchers; Japan Times (2 Sept 1992), 7.
A racial distribution of Duchenne muscular dystrophy in the West Midlands region in Britain is reported in JMG 29: 555-7. Indians having more, and Pakistanis less, than those of European-descent. On the issue of race ; T.A. Sheldon & H. Parker, "Race and ethnicity in health research", J. Public Health Medicine 14: 104-10. Letters on race and research in JAMA 267: 3150-2. There is a series of papers on Australian aboriginal health in MJA 156: 520-71.
Papers on the issue of genetic and environmental induction of insulin-dependent diabetes mellitus are in NEJM 327: 348-9; D. Cavan et al., "The genetics of type I (insulin dependent) diabetes mellitus", JMG 29: 441-6; C. Bower et al., "Birth defects in the infants of Aboriginal and non-Aboringinal mothers with diabetes in Western Australia", MJA 156: 520-4. Diabetes also appears to exert an effect on systolic blood pressure; BMJ 305: 215-9. A popular press book on genetics is reviewed in AJHG 51: 224-5. The concept of a public genetics week is discussed in AJHG 51: 220-1.
News on the genetic analysis of mammalian ear development is in TINS 15: 235-7; and see a review in W. Reardon, "Genetic deafness", JMG 29: 521-6. Genetic skin diseases involving keratin are discussed in Cell 69: 899-902. A partial gene deletion was found to be responsible for a C3 deficiency case; PNAS 89: 4957-61.
A gene found in beetles called Medea is interesting in that if a child lacks the gene, the mother with the gene will kill the offspring, a so-called selfish gene ; SA (July 1992), 15-6. Bird experiments on sexual selection are reported in Proc. Royal Soc. 249: 3-6; see also other bird studies on mate selection in NS (4 July 1992), 34-8.

A gene linked to risk for myocardial infarcation has been identified, and called atheroscherosis susceptibility gene; GEN (1 Sept 1992), 27. A screening test based on plasma homocysteine is described in JAMA 268: 877-81. A family of genes for melanocortin receptors have been cloned; Science 257: 1248-51. Genes associated with the following diseases are reported in: severe childhood autosomal recessive muscular dystrophy, Nature 359: 320-2; nephrogenic diabetes insipidus, Nature 359: 233-5, 434; Nature Genetics 2: 99-102; 103-6; atopy, Lancet 340: 381-4; lipoprotein and heart disease, BMJ 305: 472-3; tyrosinaemia, Lancet 340: 850 (822-3); ventricular arrhythmias, NEJM 327: 846-52, 885-7; hypertension, however, has many social influences, NEJM 327: 776-81, in addition to a role for angiotensinogen; Cell 71: 169-80.
Genetic causes and cancer are discussed in Lancet 340: 399-400. p53 is involved in the cell cycle and checking following irradiation; PNAS 89: 7491-5. The role of p53 in detecting DNA damage is discussed in Nature 359: 486-7. On p53 see also Cell 70: 523-6; EMBO J. 11: 3507-12, 3513-20, 3935-40. In Japan it was announced that screening for mutations in p53 from urine samples for early detection of bladder cancer will be used; Yomiuri Shimbun (28 Sept 1992), 30. Screening and counseling for breast cancer risk is described in JMG 29: 691-4. Studies on retinoblastoma (see Genetic Engineering - Animals section), Nature 359: 270-1; and neurofibromatosis type 2 is reportedly a genetically homogeneous disease; AJHG 51: 486-96. Genomic imprinting and leukemia is discussed in Nature 359: 362-3, 414-6.
Diabetes and genetics are discussed in papers; G. Velho et al., "Primary pancreatic beta-cell secretory defect caused by mutations in glucokinase gene in kindreds of maturity onset diabetes of the young", Lancet 340: 444-8; B.I.Joffe et al., "Pathogenesis of non-insulin-dependent diabetes mellitus in the black population of southern Africa", Lancet 340: 460-2, see p. 455-6.
Paternal mitochondrial inheritance in mussels is reported in Nature 359: 412-4, which is surprising because maternal sources of mitochondria are usually assumed. The mutations in mitochodria accumulate with age, see G.A. Cortopassi et al., "A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues", PNAS 89: 7370-4.
The possibility of ear hair cells being able to regenerate in some animals raises the hope that deafness may be able to be corrected; Science 257: 1344-5. An artificial middle ear is being tried in Japan, and has received permission from the Ministry of Health and Welfare; NS (3 Oct 1992), 20. The magnetic receptor mechanism of animals may be light sensitive, from newt experiments; Nature 359: 105-6, 142-4.
A review on genetics in neurology is L.P. Rowland, "The first decade of molecular genetics in neurology: changing clinical thought and practice", Annals of Neurology 32: 207-14. It includes a list of diseases with genetic markers. Genetic studies and mental illness are discussed in Science 257: 1867 which reviews a new OTA report, The Biology of Mental Disorders. A general review of schizophrenia and manic depression and their unknown genes is E.S. Gershon & R.O. Rieder, "Major disorders of mind and brain", SA (Sept 1992), 89-95 (The Sept. issue of Scientific American is a special issue on mind and brain). An editorial on genetics and schizophrenia is in BMJ 305: 664-5; and a study on brain structure is in NEJM 327: 604-12. A paper on genetics of tobacco addiction are: D. Carmelli et al., "Genetic influence on smoking - a study of male twins", NEJM 327: 829-33, 881-3. Moderate genetic influences were found.
The role of the protein ß-amyloid in Alzheimer's disease has become controversial, following the failure of researchers to repeat results which suggested that injections of the protein into the brains of rats could reverse the disease symptoms; Science 257: 1336-8; Nature 359: 268; Neurobiology of Aging (Sept. issue); BMJ 305: 667-8; Laboratory Investigation 67: 271-3; B. Regland & C.-G. Gottfries, "The role of amyloid ß-protein in Alzheimer's disease", Lancet 340: 467-9; Lancet 340: 850-1. On amyloidosis in general see PNAS 89: 7389-93. A role has been found for the molecule ATP in fast neuronal communications; Nature 359: 103-4, 144-7.
The cystic fibrosis transmembrane conductance regulator appears to be mislocated in the cell when mutated; Nature 358: 709-10; 761-4. When the protein is put into its correct cell location, in the plasma membrane, normal cell functioning resumes.
A review of the unstable regions of DNA that are associated with genetic disease, called dynamic mutations, is in Cell 70: 709-12. The genomic mutation rate for evolutionary fitness in Drosophila, a fruitfly, is reported in Nature 359: 58-60. Mutations in the cancer gene APC occur early during colorectal tumorigenesis, Nature 359: 235-7. Also on APC see Lancet 340: 626-30.

Genetic predispositions for certain types of cancer may be triggered by low levels of UV light; PNAS 89: 9534-8. The search for melanoma susceptibility genes on a region of chromosome 9 is discussed in Science 258: 1080-1, 1148-52. A marker CD44 gene may be useful for cancer screening; Lancet 340: 1053-8. A review of the role of defects of cell cycle proteins and genes in cancer cells is in Cell 71: 543-6. Common susceptibility genes for prostrate, ovarian and endometrial cancer and breast cancer are suggested in an Iceland study; BMJ 305: 855-7. The common breast and ovarian cancer dominant susceptibility gene search is discussed in JAMA 268: 2348-9; see also JAMA 268: 1896-9, 2627-8. The gene mutation causing the most common form of childhood leukemia has been identified; Cell 71: 691-700, 701-8. Mutation data from hepatocellular carcinomas suggests that p53 mutations may occur after tumorigenesis as the tumour progresses; PNAS 89: 9622-6. On the DNA binding of p53 see Cell 71: 875-86. On tumour suppressor genes see Nature 360: 210-1, 313-9. A general review is T. Sugimura, "Multistep carcinogenesis: A 1992 perspective", Science 258: 603-7. Genome amplification in cancer is reported in Science 258: 818-21.
Research to find the gene mutation causing Huntington's is discussed in Science 258: 740-1. A conference report in Science 258: 889, presents the finding that lactic acid can be used as a marker of Huntington's disease. Recent developments in molecular neurology are discussed in Nature 360: 295-6. The role of splicing and imprinting in Prader-Willi syndrome are discussed in Nature 360: 492; Nature Genetics 2: 265-9, 270-4.
A general discussion on tracking gene mutations from linkage markers is in Nature 360: 90. A common pathogenic mutation in the prion gene has been linked to two specific disease phenotypes, fatal familial insomnia and familial Creutzfeldt-Jakob disease; Science 258: 806-8. Genetics and auto-immunity is discussed in JRSM 85: 653-5. A letter in Lancet 340: 1160 questions whether schizophrenia or diabetes are genetic or zinc deficiency. On late-onset non-insulin dependent diabetes and glucokinase mutations; Lancet 340: 1316-7.
Genetic linkage studies indicate a link between Alzheimer's Disease and chromosome 14; Science 258: 668-71, 550; BMJ 305: 1108-9. A study of the APP gene locus reveals it is not generally associated with familial Alzheimer's; AJHG 51: 998-1014. New data suggests that aluminium has no role in Alzheimer's, and the appearance of aluminium in stained brain was an artefact of the staining technique using alumino-silicate contaminated reagents; Nature 360: 65-8; Science 258: 1086-7; NS (7 Nov 1992), 16. The use of computed tomography can detect Alzheimer's disease in living patients, and may be used in the future for screening; Lancet 340: 1179-83; NS (31 Oct 1992), 17; (28 Nov 1992), 19. The use of tacrine for treating some patients is suggested in studies in JAMA 268: 2523-9; NEJM 327: 1253-9, 1306-8.
Papers on presymptomatic diagnosis of myotonic dystrophy , JMG 29: 780-4; 761-5; AJHG 51: 1150-5; myotonic dystrophy in Europeans and Japanese, JMG 29: 766-7; and inheritance of Fragile X , JMG 29: 794-801; discuss diseases where the mutation grows in size between generations.
A possible molecular explanation for HLA-B53 and resistance to severe malaria is reported in Nature 360: 434-9; 417-8. This may aid vaccine development. A genetic susceptibility to multiple sclerosis has been linked to the myelin basic protein gene; Lancet 340: 987-91; and a genetic susceptibility to IgA deficiency is in PNAS 89: 10653-7. A study confirming that all cases of hemophilia A are due to mutations in the factor VIII gene is Lancet 340: 1066-7.
On cystic fibrosis chloride channel see Nature 360: 18. A letter discussing the seriousness of Down's for abortion decisions is in AJHG 51: 938-9; and on a possibility for a familial disposing factor see AJHG 51: 1015-27.

About 30 out of 1,000 residents of the town of Limone, Italy, have a mutant gene that reduces levels of high density lipoprotein ( HDL ) cholesterol in their plasma; GEN (15 Jan 1993), 1, 20. Normally low levels of HDL are associated with increased risk of heart disease , but in this case it is the opposite. It may be the case of a beneficial mutation. The gene marker for another heart disease, hypetrophic cardiomyopathy, is being used for screening; NS (2 Jan 1993), 14. In transgenic mice, arterial hardening occurs when they have the apolipoprotein (a) gene; Nature 360 (1992), 631-2, 670-2. Normal mice do not have the gene, but these transgenic mice develop atherosclerosis when on a high fat diet. The role of the angiotensiongen gene in risk for heart disease is discussed in SA (Jan 1993), 11.
Reports on the gene mutation connected with increased risk of breast cancer are in the Wall Street Journal (11 Dec 92), A1, 7. A special issue of Science includes many papers on the subject of breast cancer; Science 259: 616-38. Increased risk of breast cancer is associated with pregnancies at older age; Lancet 341: 33-5. Papers on the genetics of cancer include: Lancet 340 (1992), 1402-3. A new oncogene associated with leukemia has been reported; Science 258 (1992), 1435. The finding from transgenic mice that the gene p53 is not necessary for life has made its role in cell growth regulation less clear, though the mouse model may be useful for future studies, SA (Dec 1992), 13-4. The p53 protein is a protein kinase C substrate and a s100b-binding protein, strengthening the case for involvement in the regulation of the cell cycle; PNAS 89 (1992), 11627-31. Also on p53: regulation of hsp70, Science 259: 84-7; as a marker for colorectal adenocarcinoma Lancet 340 (1992), 1369-73.
An article reviewing the case for directed mutation finds that there is no data to show the existence of directed mutations, i.e. a higher mutation rate for more favourable mutations compared to harmful mutations; Science 259: 188-94. The gene involved in X-linked agammaglobulinaemia, an immune deficiency, has been found to be a src-gene family protein-tyrosine kinase; Nature 361: 202-3, 226-33.
One of the gene defects of Alzheimer's stimulates cells to produce more amyloid protein, suggesting that amyloid is important as has been thought; NS (19 Dec 1992), 5. The clinical prospects of Alzheimer's are reviewed in Lancet 340 (1992), 1512-5. A study in Sweden found that one third of people over 85 years old had dementia , of which one half was vascular dementia which may be treated; NEJM 328: 153-8. A study of the way that patients and doctors perceive diagnosis of Parkinson's disease is in Sociology of Health & Illness 14: 1-22. A review of the genetics of peripheral neuropathies is in TINS 16: 50-6. In many countries more people are at risk of major depression in recent birth cohorts; JAMA 268 (1992), 3098-105.
Papers on mitochondrial genetics and disease are in AJHG 51 (1992), 1179-86; BioEssays 14: 763-8; Lancet 341: 281-2. A commentary on non-inherited HLA antigens is in Lancet 341: 211. Genetic factors involved in rheumatoid arthritis and a general description of research are in Lancet 341: 283-90; BMJ 305 (1992), 1387-9. There appear to be multiple origins of phenylketonuria in Europe; AJHG 51 (1992), 1355-65. A review of PKU by a MRC working party in the U.K. is in BMJ 306: 115-9. On xeroderma pigmentosum and DNA repair see Cell 71 (1992), 887-91.
The various combinations of cystic fibrosis gene mutation alter the clinical severity; Lancet 341: 212-3. There appears to be very high heterogeneity of the CF mutation, suggesting that the goal of screening for 90-95% of mutations may be unrealistic; AJHG 51 (1992), 1344-8. Lung infection in patients with CF with Pseudomonas aeruginosa depends on the mutation in the CF gene; Lancet 341: 189-93.
Discussion of the role of lactic acid in Huntington's Disease (EEIN 3: 9) is in JAMA 268 (1992), 3286-7. Cases of Huntington Disease in black families in Africa may be more frequent than commonly assumed; AJMG 44 (1992), 762-6. A prevalence of 0.5-1 per 100,000 in a region of Zimbabwe is suggested. Three independent groups have cloned the gene responsible for Menkes disease; Nature 361: 98; Nature Genetics 3: 7-25. Two simple molecules, NO and CO have been shown to be brain messenger signals; Science 258 (1992), 1862-3; 259: 309. The debate over whether neurotoxin is the cause of consequence of inflammatory brain diseases is in Science 259: 25-6.
The severity of muscular dystrophy varies with the size of the mutated region, and some gene mutations increase between generations. A contrary example is reported in K.L. O'Hoy et al., "Reduction in the size of the myotonic dystrophy trinucleotide repeat mutation during transmission", Science 259: 809-12. A letter on maternal origins of myotonic dystrophy is in Lancet 341: 236-7. The use of prenatal testing for carriers who have point mutations in dystrophin is suggested in Lancet 341: 273-5.
A Japanese company, Imax, has started producing toilets that detect diabetes ; NS (19 Dec 1992), 20. These will be used first in geriatric hospitals. Insulin resistance and weight appear to be linked; Lancet 340 91992), 1452-3. A criticism of gestational diabetes screening is in BMJ 306: 37-8. A polymorphism called Xba1 of the glyogen synthase gene has been found to be associated with non-insulin dependent diabetes mellitus; NEJM 328: 10-4, 56-7. A link to a mitochondrial gene mutation is suggested in Lancet 340 (1992), 1376-9.

The gene causing Huntington's disease has been cloned, and named Huntingtin, after many years of an international project; The Huntington's Disease Collaborative Research Group, "A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's Disease chromosomes", Cell 72, 971-83, 817-8. The mutation involves an unstable region of DNA, which grows over transmission as found for fragile X syndrome, spino-bulbar muscular atrophy and myotonic dystrophy. There is correlation between increased length of the mutated region and earlier onset of the disease. The early study, on 75 patients, suggests the mutation is increased more in male transmission than female. See also Y.P. Goldberg et al., "Identification of an Alu retrotransposition event in close proximity to a strong candidate gene for Huntington's disease", Nature 362: 370-3; NS (27 March 1992), 7; Science 260: 28-30; BMJ 306: 878-9; Time (5 April 1993), 13.
A newly recognised genetic disease called ovalocytosis has been identified in Asians, which makes egg-shaped red blood cells which are more resistant to malaria ; JAMA 269: 1765. The mutation makes the cell membranes to rigid for the parasite to enter.
Mutations in the putative glucose receptor of pancreas beta cells, glucokinase, have been found to be associated with maturity onset diabetes of the young; P. Frogeul et al., "Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of Diabetes Mellitus", NEJM 328: 697-702, 729-31; PNAS 90: 784-5; BMJ 306: 532-3. A review of research looking at the association between diabetes and HLA is in Nature 362: 478. Letters on the question of screening for diabetes are in CMAJ 148: 11-3.
It has been suggested that intermarriage may have some benefits for the genome, by flushing out recessive alleles; NS (27 Feb 1993), 9; Science 259: 1252. However, the 1.5-9% higher mortality shown in children of first cousin marriages is significant in some countries. On the effects of population mixing, and inbreeding, see AJMG 46: 254; BMJ 306: 930.
Research on Alzheimer's drugs is reviewed in TIBTECH 11: 49-55; Nature 362: 14-5. On the epidemiology of Alzheimer's see BMJ 306: 680-3; Annals Neurology 33: 528-66. A gene linked to Lou Gehrig's disease, a degenerative nerve disorder, has been found by a group of 31 scientists in 8 American institutes; Nature 20-1, 59-62; BMJ 306: 672-3.
A survey of five linkage sites suggested to be markers for schizophrenia has found them all negative; AJHG 52: 327-34. Some clinical problems of schizophrenia are discussed in Lancet 341: 531-5, 536-8. Mutations in the enzyme lysozyme have been found to cause hereditary systemic amyloidosis , Nature 362: 553-7. A supplement to Cell and Neuron for January is on neuro-transmitters. Genes involved in olfaction in catfish are reported in Cell 72: 657-66, 667-80.
The list of risk factors for heart disease continues to grow, including baldness; Time (8 March 1992), 42; and dental disease; BMJ 306: 688-91; and genetic factors, Amer. J. Med. 94: 77-84. A review of the genetic factors involved in predisposition to thrombosis is in Cell 72: 477-80. Letters on heterozygote advantage , a "frisky genotype" against primary hypertension are in Lancet 341: 700.
The genetics of retinal disorders is being understood by recent papers; Nature 362: 92. Mixed results have been obtained from a study of antigen feeding as an approach to treating multiple sclerosis; Science 259: 1263, 1321-. Several papers report the discovery of genes involved in X-linked agammaglobulinaemia and X-linked immunodeficiency with hyper-IgM; Nature 361: 226-33, 494, 539-41, 541-3; Science 259: 990-3; Cell 72: 291-300.
Papers on the relationship between severity and genetic mutation in cystic fibrosis include Nature 362: 106, 160-4; see also BMJ 306: 549-52.
Presymptomatic diagnosis of spinal muscular atrophy is now possible; AJMG 45: 408-11. A reduction in the size of the myotonic dystrophy mutation during transmission is reported in Science 259: 809-12; AJMG 45: 401-7. A review is L.J. Ptacek et al., "Genetics and physiology of myotonic muscle disorders", NEJM 328: 482-9. The gene associated with X-linked adrenoleukodystrophy has also been reported, Nature 361: 726-30.
A link between cancer and hypertension is slowly being established; BMJ 306: 598-9, 609-11, 622-3. The loss of the gene IGF-1, interferon regulatory factor-1, has been linked to human leukemia and myelodysplasia; Science 259: 968-71. A benefit for patients is found in another gene, A. Nakagawara et al., "Association between high levels of expression of the TRK gene and favourable outcome in human neuroblastoma", NEJM 328: 847-54.
A review of genomic imprinting and uniparental disomy is in AJMG 46: 16-25. There is sometimes loss, or relaxation, of imprinting, and this is linked to cancer; Nature 362: 747-9, 749-51. Genetic diseases and the peroxisome are discussed in Nature 361: 682-3.
The genetics of circadian rhythms is reviewed in U.S. News & World Report (18 Jan 1993), 67-9; BMJ 306: 448-51. Reviews of the methods of mutations in DNA is in SA (March 1992), 88-96; L. Partidge & N.H. Barton, "Optimality, mutation and the evolution of ageing", Nature 362: 305-11; T. Lindahl, "Instability and decay of the primary structure of DNA", Nature 362: 709-15. On the question of sexual differences in mutation rate see Nature 362: 745-7. Papers discussing the genetics of speciation and Haldane's rule are in Nature 361: 696-7, 532-3.

A review of the involvement of triple repeat sequence mutations in Fragile X syndrome, spinobulbar muscular atrophy, myotonic dystrophy, and Huntington's disease, is in Science 260: 1422-3. On analysis of the protein associated with Fragile X see Nature 363: 722-4; on guidelines for diagnosis, JMG 30: 410-3; and on neurobehavioural effects, AJHG 52: 884-94. The use of triplet length to predict myotonic dystrophy mutation is reported from 241 patients in JAMA 269: 1960-5; also see AJHG 52: 875-83.
The gene linked to breast cancer, BRCA1, and genetic counseling is discussed in many papers in AJHG 52: 677-798; Lancet 341: 1060-1; JAMA 269: 1970-5, 1975-80. On treatment of breast cancer see NEJM 328: 1633-4.
Links between exclusion from the nucleus of a carbohydrate binding protein 35 (Mac-2) and colon carcinoma are reported in PNAS 90: 3466-70; also on mapping of a new colon cancer genes, Science 260: 751-2, 810-2, 812-6, 816-9; Time (17 May 1993), 52; Newsweek (17 May 1993), 46; BMJ 306: 1291; and on somatic mutations in simple repeated sequences see Nature 363: 558-61.
A gene for neurofibromatosis -2 has been identified, G.A. Rouleau et al.,, "Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2", Nature 363: 515-21, and a review of dominantly inherited genes predisposing to cancers is on p.495-6. Predisposition to cancer caused by gene replacement of Hras1 is reported in Science 260: 1524-7; also on ras , p. 767-8. The identification of a new tumour suppressor gene is, F. Latif et al., "Identification of the von Hippel-Lindau Disease tumour suppressor gene", Science 260: 1317-20, 1235. A region of chromosome 11 has been shown to arrest the growth of cancer; Science 260: 361-4. On p53 mutation in Hodgkin disease, PNAS 90: 2817-21; p53 has been found to be an unusally shaped tetramer protein, PNAS 90: 3319-23. Also on p53 see Nature 362: 786-7, 847-52; Amer. J. Med. Sciences 305: 275-9. In utero oncogene rearrangements are reported in infant leukemias; Nature 363: 358-60. Mutations of the RET gene are found to be linked to endocrine cancer; Nature 363: 458-60. On treatment of tumours by making them more immunogenic see PNAS 90: 4332-3.
Genetic predisposition to hypertension is a risk factor for developing hypertension when undergoing treatment with the protein EPO; Amer. J. Medicine 94: 401. On advances in biology of cardiovascular disease and atherosclerosis see Science 260: 916-7; Nature 362: 801-9.
A report earlier in the year (Nature Genetics, February; Human Genome News, March, 10), shows that different mutations in a single gene can cause two unrelated genetic diseases. The gene, PAX3 is responsible for congenital deafness Waardenburg syndrome, and for a soft tissue sarcoma, alveolar rhabdomyosarcoma. Multiple sclerosis (MS) does not appear to be linked to the myelin basic protein gene; Lancet 341: 1179-81; also, SA (May 1993), 81-2. A book review on The Genetics of Asthma is BMJ 306: 1622. On diabetes and vasopressin and other genes, NEJM 328: 1534-7, 1538-41, 1562, 1568-9; PNAS 90: 1932-6, 2633-5; BMJ 306: 1198.
The glaucoma gene has been mapped to chromosome 1; Nature Genetics 4: 47-50; JAMA 269: 2715. Gaucher's disease treatment is discussed in letters to NEJM 328: 1564-8; Amer. J. Med. Sciences 305: 331-44. On the role of motor neurons and neurofilaments in motor neuron disease and sickness see Cell 73: 1-3, 23-33. On the pathology of cystic fibrosis see Lancet 341: 1065-9, 1070-4; and on the further characterisation of the protein, Nature 363: 263-6. The loss of telomeris DNA during aging of trisomy 21 ( Down's ) persons is suggested to be one link to the aging process; AJHG 52: 657-60, 661-7. A mutation in the IL-2 receptor results in X-linked severe combined immunodeficiency ( SCID ) in humans; Cell 73:147-57; 5-8.
A screening approach that revealed many genes with possible links to neural plasticity (modified response to an altered input) is in Nature 363: 718-22. Hyperactivity has also been reported to be associated with genes; NEJM (8 April 1993); Science 260: 295. A high intrachromosomal mutation rate is reported in the neurological disease Ataxia-Telangiectasia, Science 260: 1327-30.
A protein thought to be associated with Alzheimer's , amyloid precursor protein (APP) has now also been found in high levels in undiseased brains; GEN (15 Feb 1993), 1, 13. The linkage of familial Alzheimer's to chromosome 14 in two large early-onset families is reported in AJMG 48: 63-6; see also Nature 362: 839-41;Time (21 June 1993), 50. In general see NS (19 June 1993), 22-6. A new therapy using an anti-inflamatory drug indomethacin is suggested to work from six months progress in a clinical study, Science 260: 1719-20.
Genetic imprinting is reviewed in NS (22 May 1993), 34-8; counterparts of at least four human genes are detected in mouse so far; Nature 363: 94. A review of the role of methylation in imprinting is in Science 260: 309-10. A book review of Epidemiology of Congenital Malformation s is in AJHG 52: 1019-20.
A paper on the biological clock is in PNAS 90: 4087-91. The homing mechanism of birds is reviewed in Nature 363: 112-3. The use of RNA editing as a source of genetic variation is reported in Nature 363: 179-82. The rates of mutation in RNA viruses are compared in PNAS 90: 4171-5.

A gene that is linked to Alzheimer's disease has been identified, the ApoE4 allele of the apolipoprotein E gene; E. Corder et al., "Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer disease in late onset families", Science 261: 921-3 ; NS (21 Aug 1993), 17; Lancet 342: 426. It is thought that the protein binds to beta amyloid resulting in accumulations in the brain, but it is unknown. In a Duke University study of 42 families with late onset Alzheimer's they found if there is no ApoE4, 20% got the disease with an average age of 84 years at onset. With one copy, 47% got it at average 76 years, and with 2 copies, 91% got it with average onset age of 68 years. Also on Alzheimer's, JMG 30: 640-6;PNAS 90: 6381-4; Cell 73: 1055-8; Biotechnology 11: 774; Science 260: 1719-20.
On cancer genes see reviews on tumour suppressor genes in PNAS 90: 5893-5; a special issue of FASEB J : 7: 819-30+; Science 260: 1524-7, 261: 428; Nature 364: 308-13; BMJ 307: 164-8, 277-8; JAMA 270: 338-43. The mutation of p53 appears to increase resistance to ionizing radiation, PNAS 90: 5742-6. A link between cancer risk and mutations in the HRAS1 minisatellite locus is reported in NEJM 329: 517-23. On modifying genes in neurofibromatosis, AJHG 53: 301-4, 305-13.
The genetics of aging is reviewed in Human Genetics 91: 519-26; Biotechnology 11: 787-92. Genetic susceptibility to common diseases is reviewed in MJA 158: 783-6. On genes and behaviour in nematodes, Nature 364: 282-3, +. Genetic studies in behaviour (see also the ethics section below) include: linkage studies in general, AJMG 48: 71-3, 74-7794-102; schizophrenia, AJMG 48: 83-6, 90-3; Lancet 342: 117-8.
On trinucleotide repeat sequences, Lancet 342: 385-6; Science 260: 1422-3; and in Fragile X , Cell 74: 127-34; JMG 30: 647-50; and on population screening for it,BMJ 306: 1699. The protein product of Fragile X gene is probably a RNA-binding protein, Cell 74: 291-8; see also AJMG 48: 112-21, 685-6.
Papers on the genetics of other diseases include: JAMA 270: 246-8; AJHG 53: 6-15; deafness, AJMG 46: 486-91; multiple sclerosis and T cell receptor, Nature 364: 243-7, 187-8; Gaucher disease, PNAS 90: 5384-90; ocular disorders, MJA 158: 615-8; connective tissue disorders, MJA 158: 678-80; polycystic kidney disease, NEJM 329: 332-42; JMG 30: 583-8; long QT syndrome, Science 260: 1960-2. A book on the genetics of biological rhythms is reviewed in Science 261: 772-3. On elastic DNA elements, mobile introns, etc. that vary the inheritance in humans, NEJM 329: 571-3; PNAS 90: 5379-81, 5534-8.

Further papers associating a known gene on chromosome 19 with Alzheimer's (Science 261: 921-3, 828-9,EEIN 3: 66) are J. Poirier et al., "Apolipoprotein E polymorphism and Alzheimer's disease", Lancet 342: 697-9, 625, 696, 710-1, 737-8. More on the APO E4 allele linked to Alzheimer's in GEN (1 Sept 1993), 27. A general review of Alzheimer's and genetic factors is TINS 16: 398-402; and on data to show that chromosome 14 is not responsible for late onset Alzheimer's see AJHG 53: 619-28.
Expansion of the Huntington's gene mutation is reported in sporadic cases in Nature Genetics 5: 168-73, see also p. 174-9. The destabilization of simple repetitive DNA in yeast by mutations in DNA repair is reported in Nature 365: 274-6, 207-8; Cell 74: 955-6. The mutations may occur by slippage of the enzymes along the DNA.
A genetic link to schizophrenia is claimed in P. Seeman et al., "Dopamine D4 receptors elevated in schizophrenia", Nature 365: 441-5, 393. The level of D4 receptors is 6 time greater in schizophrenia patients, suggesting that the functional coupling of the dopamine receptors is incorrect in this disease. Genetics and mental disease is discussed in TINS 16: 387-9.
A theoretical paper is T.J. Crow, "Sexual selection, Machiavellian intelligence, and the origins of psychosis ", Lancet 342: 594-8. A analytical paper on sex ratio and natural selection is in Annals Human Genetics 57: 211-9. A letter on the designation of mutations and definitions is AJHG 53: 783-5.
Research on the genetics of inherited migraines progressed with a link being made to a genetic marker on chromosome 19; Nature Genetics 5: 40-5; Nature 365: 86. Mutations in G-protein coupled receptors are found to be the causes of two genetic diseases in Nature 365: 603-4, 649-54. The disease mechanism of the mutation of superoxide dismutase behind amyloid lateral sclerosis is reported in Science 261: 986, 1047-9. Several articles on trends in the genetic mutations of Duschenne muscular dystrophy patients are in JMG 30: 713-27, 728-36, 737-744, 745-51. General disease mapping techniques in isolated populations using the example of Finland are reviewed in JMG 30: 857-65.
Discussion of breast cancer genetics is in Nature Genetics 5: 101-2; JAMA 270: 1563-8, 1602-3, and familial cancer genes are summarised in Nature Genetics 5: 103-4, 109-10. The number of p53 associated proteins continues to grow, Nature 365: 17-8, 79-82; Cell 74: 957-67. Also on cancer genes, Lancet 342: 469-71, 754-5, 848-50; NEJM 329: 958-9; Science 261: 1197-9, 1385-7; BMJ 307: 542, 579-80. On genetic controls over cell death, Cell 74: 777-79.

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