Jacquie Greenberg

Linkage of Usher syndrome type I gene (USH1B) to the long arm of chromosome 11

Usher syndrome is the most commonly recognized cause of combined visual and hearing loss in technologically developed countries. There are several different types and all are inherited in an autosomal recessive manner. There may be as many as five different genes responsible for at least two closely related phenotypes. The nature of the gene defects is unknown, and positional cloning strategies are being employed to identify the genes. This is a report of the localization of one gene for Usher syndrome type I to chromosome 11q, probably distal to marker D11S527. Another USH1 gene had been previously localized to chromosome 14q, and this second localization establishes the existence of a new and independent locus for Usher syndrome.

The Guanine-Thymine Dinucleotide Repeat Polymorphism Within the Tenascin-C Gene Is Associated With Achilles Tendon Injuries

Background Although there is a high incidence of tendon injury as a result of participation in physical activity, the mechanisms responsible for such injuries are poorly understood. Investigators have suggested that some people may have a genetic predisposition to develop tendon injuries; in particular, genes on the tip of the long arm of chromosome 9 might, at least in part, be associated with this condition. The tenascin-C gene, which has been mapped to chromosome 9q32-q34, encodes for a structural component of tendons. Hypothesis The tenascin-C gene is associated with Achilles tendon injury. Study Design Case control study; Level of evidence, 3. Methods A total of 114 physically active white subjects with symptoms of Achilles tendon injury and 127 asymptomatic, physically active white control subjects were genotyped for the guanine-thymine dinucleotide repeat polymorphism within the tenascin-C gene. Results A significant difference in the allele frequencies of this polymorphism existed between the 2 groups of subjects (χ2 = 51.0, P =. 001). The frequencies of the alleles containing 12 repeats (symptomatic group, 18.9% vs control group, 10.2%) and 14 repeats (symptomatic group, 9.2% vs control group, 0.8%) were significantly higher in the symptomatic group, while the frequencies of the alleles containing 13 repeats (symptomatic group, 8.8% vs control group, 24.0%) and 17 repeats (symptomatic group, 7.5% vs control group, 20.1%) were significantly lower in this same group. Subjects who were homozygous or heterozygous for the underrepresented alleles (13 and 17 repeats) but who did not possess an overrepresented allele (12 and 14 repeats) may have a lower risk of developing Achilles tendon injuries (odds ratio, 6.2; 95% confidence interval, 3.5-11.0; P <. 001). Conclusions The guanine-thymine dinucleotide repeat polymorphism within the tenascin-C gene is associated with Achilles tendon injury. Alleles containing 12 and 14 guanine-thymine repeats were overrepresented in subjects with tendon injuries, while the alleles containing 13 and 17 repeats were underrepresented. Clinical Relevance Persons who have variants of the tenascin-C gene with 12 and 14 guanine-thymine repeats appear to have a 6-fold risk of developing Achilles tendon injuries.

The hereditary adult-onset ataxias in South Africa.

There is little data on the spectrum and frequencies of the autosomal dominant spinocerebellar ataxias (SCAs) from the African continent. We undertook a large prospective population-based study over a 10-year period in South Africa (SA). Affected persons were clinically evaluated, and the molecular analysis for the SCA1, 2, 3, 6 and 7 expansions was undertaken. Of the 54 SA families with dominant ataxia, SCA1 accounted for 40.7%, SCA2 for 13%, SCA3 for 3.7%, SCA6 for 1.9%, SCA7 for 22.2% and 18.5% were negative for all these mutations. The frequency of the SCA1 and SCA7 expansions in SA represents one of the highest frequencies for these expansions reported in any country. In this study, the SCA7 mutations have only been found in SA families of Black ethnic origin.

Genetic Heterogeneity of Usher Syndrome: Analysis of 151 Families with Usher Type I

Usher syndrome type I is an autosomal recessive disorder marked by hearing loss, vestibular areflexia, and retinitis pigmentosa. Six Usher I genetic subtypes at loci USH1A-USH1F have been reported. The MYO7A gene is responsible for USH1B, the most common subtype. In our analysis, 151 families with Usher I were screened by linkage and mutation analysis. MYO7A mutations were identified in 64 families with Usher I. Of the remaining 87 families, who were negative for MYO7A mutations, 54 were informative for linkage analysis and were screened with the remaining USH1 loci markers. Results of linkage and heterogeneity analyses showed no evidence of Usher types Ia or Ie. However, one maximum LOD score was observed lying within the USH1D region. Two lesser peak LOD scores were observed outside and between the putative regions for USH1D and USH1F, on chromosome 10. A HOMOG chi(2)((1)) plot shows evidence of heterogeneity across the USH1D, USH1F, and intervening regions. These results provide conclusive evidence that the second-most-common subtype of Usher I is due to genes on chromosome 10, and they confirm the existence of one Usher I gene in the previously defined USH1D region, as well as providing evidence for a second, and possibly a third, gene in the 10p/q region.

Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations

Waardenburg syndrome (WS) type 1 is an autosomal dominant disorder characterized by sensorineural hearing loss, pigmentary abnormalities of the eye, hair, and skin, and dystopia canthorum. The phenotype is variable and affected individuals may exhibit only one or a combination of several of the associated features. To assess the relationship between phenotype and gene defect, clinical and genotype data on 48 families (271 WS individuals) collected by members of the Waardenburg Consortium were pooled. Forty-two unique mutations in the PAX3 gene, previously identified in these families, were grouped in five mutation categories: amino acid (AA) substitution in the paired domain, AA substitution in the homeodomain, deletion of the Ser-Thr-Pro-rich region, deletion of the homeodomain and the Ser-Thr-Pro-rich region, and deletion of the entire gene. These mutation classes are based on the structure of the PAX3 gene and were chosen to group mutations predicted to have similar defects in the gene product. Association between mutation class and the presence of hearing loss, eye pigment abnormality, skin hypopigmentation, or white forelock was evaluated using generalized estimating equations, which allowed for incorporation of a correlation structure that accounts for potential similarity among members of the same family. Odds for the presence of eye pigment abnormality, white forelock, and skin hypopigmentation were 2, 8, and 5 times greater, respectively, for individuals with deletions of the homeodomain and the Pro-Ser-Thr-rich region compared to individuals with an AA substitution in the homeodomain. Odds ratios that differ significantly from 1.0 for these traits may indicate that the gene products resulting from different classes of mutations act differently in the expression of WS. Although a suggestive association was detected for hearing loss with an odds ratio of 2.6 for AA substitution in the paired domain compared with AA substitution in the homeodomain, this odds ratio did not differ significantly from 1.0.

Familial streptomycin ototoxicity in a South African family: a mitochondrial disorder.

The vestibular and ototoxic effects of the aminoglycoside antibiotics (streptomycin, gentamycin, kanamycin, tobramycin, neomycin) are well known; streptomycin, in particular, has been found to cause irreversible, profound, high frequency sensorineural deafness in hypersensitive persons. Aminoglycoside ototoxicity occurs both sporadically and within families and has been associated with a mitochondrial DNA (mtDNA) 1555A to G point mutation in the 12S ribosomal RNA gene. We report on the molecular analysis of a South African family with streptomycin induced sensorineural deafness in which we have found transmission of this same predisposing mutation. It is now possible to identify people who are at risk of hearing loss if treated with aminoglycosides in the future and to counsel them accordingly. In view of the fact that aminoglycoside antibiotics remain in widespread use for the treatment of infections, in particular for tuberculosis, which is currently of epidemic proportions in South Africa, this finding has important implications for the family concerned. In addition, other South African families may potentially be at risk if they carry the same mutation.

Alström syndrome: further evidence for linkage to human chromosome 2p13

Abstract. Alström syndrome is a rare autosomal recessive disorder characterized by retinal degeneration, sensorineural hearing loss, early-onset obesity, and non-insulin-dependent diabetes mellitus. The gene for Alström syndrome (ALMS1) has been previously localized to human chromosome 2p13 by homozygosity mapping in two distinct isolated populations – French Acadian and North African. Pair-wise analyses resulted in maximum lod (logarithm of the odds ratio) scores of 3.84 and 2.9, respectively. To confirm these findings, a large linkage study was performed in twelve additional families segregating for Alström syndrome. A maximum two-point lod score of 7.13 (θ=0.00) for marker D2S2110 and a maximum cumulative multipoint lod score of 9.16 for marker D2S2110 were observed, further supporting linkage to chromosome 2p13. No evidence of genetic heterogeneity was observed in these families. Meiotic recombination events have localized the critical region containing ALMS1 to a 6.1-cM interval flanked by markers D2S327 and D2S286. A fine resolution radiation hybrid map of 31 genes and markers has been constructed.

A South African mixed ancestry family with Huntington disease-like 2: Clinical and genetic features

Huntington disease‐like 2 (HDL2) is a neurodegenerative disorder caused by an expansion of a CTG repeat in the junctophilin‐3 gene (JPH3). A limited number of HDL2 families have been reported, all of apparently Black African ancestry. We report on a South African family that presented with progressive dementia and a movement disorder affecting numerous family members. Genotyping of the JPH3 CTG repeat revealed pathogenic expansions in three affected individuals. Whereas HDL2 is thought to be clinically indistinguishable from Huntington disease (HD), 2 of the patients in this study presented with clinical symptoms that differed substantially from HD; one had myoclonus and the other had Parkinsonism. Moreover, brain magnetic resonance imaging scans of these patients showed imaging features atypical for HD. Mitochondrial DNA and Y‐chromosome DNA analysis on a family member showed that his maternal and paternal ancestries are typical of that found among the South African mixed ancestry or colored population. A difference in the distribution of CTG repeats between Caucasian and Black individuals was detected. We conclude that the phenotype of HDL2 is broad and can differ from that of typical HD. The diagnosis therefore should be considered in a wide spectrum of neuropsychiatric and abnormal movement presentations.

Retinitis pigmentosa in Southern Africa

Greenberg J, Bartmann L, Ramesar R, Beighton P. Retinitis pigmentosa in Southern Africa.

Hearing Impairment and Pigmentary Disturbancea

Hearing impairment is a variable manifestation of several heritable conditions in which pigmentation of the skin or eyes is abnormal. Some of these disorders are well recognized although uncommon, while others are virtually private syndromes. Practical issues concerning the major conditions of this type are reviewed in this article on a basis of a survey of 4452 profoundly deaf children attending special schools in Southern Africa, together with investigations in affected families. The Waardenburg syndrome (WS), which is the most common deafness-depigmentation disorder, was present in 121 (2.7%) of the 4452 deaf scholars. Further studies in 7 multigeneration affected families confirmed phenotypic variability and indicated a need for internationally agreed diagnostic criteria. In 4 Cape Town families of mixed ancestry the WS-I gene was linked to the 2q37 locus, but in another large kindred no linkage could be demonstrated. Nonallelic heterogeneity is possible. There is uncertainty concerning possible interrelationship between WS and piebaldism. The phenotypic consistency of a South African family in which 7 persons in 3 generations had gross piebaldism in the absence of disturbance of hearing or involvement of the eyes and periorbital structures is suggestive that this disorder and WS are separate entities. Molecular investigations indicate that the gene for piebaldism in this kindred is not situated at the WS-I locus 2q37. Deafness and hyperpigmentation are present in neurofibromatosis type II (acoustic neuromata) and the multiple lentigines syndrome, while retinal pigmentation is a feature of the Usher syndrome. This latter entity is apparently much less common in Southern Africa than in other parts of the world.