D. J. Shaw

Assignment of human ferritin genes to chromosomes 11 and 19q13.3→19qter

SummaryExtracts of hamster-human and mouse-human hybrids, some with translocations involving chromosome 19, have been assayed for both human spleen ferritin (rich in L subunits) and human heart ferritin (rich in H subunits). Hybrid lines retaining part of the long arm of chromosome 19 including the region 19q13.3→19qter produced human “L” type ferritin. This confirms the previous assignment of the “ferritin gene” to chromosome 19 (Caskey et al. 1983). However, lines retaining chromosome 11 were found to contain human “H” type ferritin suggesting that the gene for the “H” subunit is on this chromosome. The presence of chromosome 6 was not necessary for the expression of either “H” or “L” type human ferritin. It thus seems unlikely that the gene for idiopathic haemochromatosis is a ferritin gene.

Genomic organization and transcriptional units at the myotonic dystrophy locus.

The genomic structure and apparently complete coding sequence of the myotonic dystrophy protein kinase gene have been determined. The gene contains 15 exons distributed over about 13 kb of genomic DNA. It codes for a protein of 624 amino acids with an N-terminal domain highly homologous to cAMP-dependent serine-threonine protein kinases, an intermediate domain with a high alpha-helical content and weak similarity to various filamentous proteins, and a hydrophobic C-terminal segment. Located in close proximity is a second gene, coding for a transcript of about 3 kb, that is homologous to the gene DMR-N9 in the corresponding mouse locus, but has no homologies to other known genes or proteins. Strong expression of the latter gene in brain suggests that it may have a role in the development of mental symptoms in severe cases of the disease.

The apolipoprotein CII gene: Subchromosomal localisation and linkage to the myotonic dystrophy locus

SummaryThe human apolipoprotein CII gene probe detects a restriction fragment length polymorphism located on chromosome 19. We have investigated the linkage of this polymorphism to the myotonic dystrophy locus in families. The two lici are closely linked with a maximum Lod score of 7.877 at 4% recombination. The close linkage and informativeness of the APOC2 polymorphism suggest that this probe may be of use for presymptomatic diagnosis of the myotonic dystrophy gene. The APOC2 gene was localised to the region 19p13–19q13 using somatic cell hybrids, providing further evidence that the myotonic dystrophy locus is situated in the central region of chromosome 19.

Linkage disequilibrium in Huntington's disease: an improved localisation for the gene.

The search for the Huntingtons disease gene has recently concentrated on the telomere of the short arm of chromosome 4. The evidence suggesting this position has been based on single crossover events, but there is conflicting evidence regarding the position of the gene relative to the most terminal markers. We have found significant linkage disequilibrium between the markers D4S98 (probe BS731B-C) and D4S95 (probe BS674E-D) and HD, which supports a localisation for the gene proximal to D4S90 and makes a telomeric localisation unlikely. This disequilibrium may also prove to be important in the future in allowing modification of risk estimates based on genetic linkage.

Localization of genes encoding apolipoproteins CI, CII, and E to the p13----cen region of human chromosome 19.

SummaryThe genes encoding apolipoproteins CI, CII, and E have been previously localized to chromosome 19. By use of rodent-human hybrid cell lines containing translocations of chromosome 19 we have now mapped these three genes to the region 19p13–19q13 and most probably 19p13–19 cen. The clustering of APOC1, APOC2, and APOE must reflect their common evolutionary background and suggests that they may be coordinately regulated. Polymorphisms detected for any one gene will be useful for inheritance studies of all three.

Genetic linkage relationships of seven DNA probes with Duchenne and Becker muscular dystrophy

SummaryThe inheritance of seven restriction fragment length polymorphisms detected by DNA probes has been studied in families with Duchenne and Becker muscular dystrophies (DMD and BMD). The probes used have all been mapped to the short arm of the X-chromosome, four being distal and three proximal to the disease loci located within the Xp21 region. Linkage analysis of the DNA polymorphisms in relation to the two disorders showed similar genetic distances. Data obtained from DMD and BMD families have been combined to give more precise values for the different recombination fractions. Combined use of these polymorphic DNA markers will be of practical value in the genetic counselling of women at risk for Duchenne and Becker muscular dystrophy.

Genetic linkage between Huntington's disease and the DNA polymorphism G8 in South Wales families.

Analysis of the polymorphism shown by the DNA probe G8 in eight South Wales families with Huntingtons disease has confirmed close genetic linkage between this marker and the disorder, the most likely genetic distance being two centimorgans (cM). The closeness of the linkage suggests that G8 may have clinical applications in genetic prediction for this condition.

A new DNA marker (D4S90) is located terminally on the short arm of chromosome 4, close to the Huntington disease gene.

Genetic linkage studies have mapped Huntingtons disease (HD) to the distal portion of the short arm of chromosome 4 (4p16.3), 4 cM distal to D4S10 (G8). To date, no definite flanking marker has been identified. A new DNA marker, D4S90 (D5); which maps to the distal region of 4p16.3, is described. The marker was used in a genetic linkage study in the CEPH reference families with seven other markers at 4p16. The study, together with knowledge of the physical map of the region, places D4S90 as the most distal marker, 6 cM from D4S10. A provisional linkage study with HD gave a maximum lod score of 2.14 at a theta of 0.00 and no evidence of linkage disequilibrium. As D4S90 appears to be located terminally, it should play an important role in the accurate mapping and cloning of the HD gene.

Regional localisations and linkage relationships of seven RFLPs and myotonic dystrophy on chromosome 19

SummaryWe have studied the genetic linkage relationships of seven DNA polymorphisms on chromosome 19, with each other and with the myotonic dystrophy locus. The DNA sequences were localised to various regions of the chromosome using translocations in somatic cell hybrids. These results provide the basis for a linkage map of most of chromosome 19, and suggest that the myotonic dystrophy locus is close to the centromere.

Minimal expression of myotonic dystrophy: a clinical and molecular analysis.

A clinical and molecular study is reported of 83 patients considered to be minimally affected with myotonic dystrophy (DM). These had been identified in three ways: 60 subjects were identified on clinical grounds and were divided into those with and those without neuromuscular involvement (groups I and II); nine subjects were at high risk of carrying the DM gene but had a normal phenotype (group III); and 14 were parents of definitely affected patients where neither parent showed clinical abnormalities (group IV). PCR analysis of the CTG repeat in the DM gene showed a range of 70 to 230 repeats for the younger at risk patients in group III, while the asymptomatic gene carriers in group IV had 53 to 60 repeats. The sensitivity of diagnosis by EMG was found to be 39%. For ophthalmic signs this was 97.5%. This suggests that assignment on the basis of minimal clinical features carries a significant error. Molecular analysis, in conjunction with established clinical investigations, should prove valuable in the identification and exclusion of minimal myotonic dystrophy.