A Complete Association of an intronic SNP rs6798742 with Origin of Spinocerebellar Ataxia Type 7-CAG Expansion Loci in the Indian and Mexican Population (original) (raw)
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Indian Journal of Medical Research, 2015
Background & objectives: spinocerebellar ataxia 7 (sCA7) is a rare form of neurodegenerative disorder with the clinical manifestation of cerebellar ataxia and retinal degeneration. In this study we describe the clinico-genetic characteristics of nine sCA7 families of Indian origin and cross compare these with other available worldwide studies. Methods: Thirty five individuals from nine SCA7 families were clinico-genetically characterized and CAG repeat distribution analysis was carried out in 382 control DNA samples from healthy controls (derived from 21 diverse Indian populations based on ethnic and linguistic and geographical location). Results: Of the nine families studied, 22 affected individuals and one asymptomatic carrier were identified. The average age at disease onset was 23.4±12.6 yr. The length of expanded CAG ranged from 40-94 with mean value of 53.2±13.9. The main clinical findings in affecteds individuals included cerebellar ataxia, and retinal degeneration along with hyper-reflexia (95%), slow saccades (85%) and spasticity (45%). Analysis of the association of number of CAG repeats with disease onset revealed that <49 repeats were associated with earlier age at onset in south East Asians compared to European populations. Further analysis of CAG repeats from 21 diverse Indian populations showed pre-mutable repeats (28-34) alleles in the IE-N-LP2 population. Six of the nine families identified in this study belonged to the same ethnic population. Interpretations & conclusion: Our results show that presenece of SCA7 is relatively rare and confined to one ethnic group from Haryana region of India. We observed a homogeneous phenotypic expression of sCA7 mutation as described earlier and an earlier age of onset in our patients with CAG <49. The identification of pre-mutable allele in IE-N-LP2 suggests this population to be at the risk of SCA7.
The American Journal of Human Genetics, 1998
To test the hypothesis that the frequencies of normal alleles (ANs) with a relatively large number of CAG repeats (large ANs) are related to the prevalences of the dominant spinocerebellar ataxias (SCAs)-SCA types 1, 2, 3 (Machado-Joseph disease), 6, and dentatorubralpallidoluysian atrophy (DRPLA)-we investigated the relative prevalences of these diseases in 202 Japanese and 177 Caucasian families and distributions of the number of CAG repeats of ANs at these disease loci in normal individuals in each population. The relative prevalences of SCA1 and SCA2 were significantly higher in Caucasian pedigrees (15% and 14%, respectively) than in Japanese pedigrees (3% and 5%, respectively), corresponding to the observation that the frequencies of large ANs of SCA1 (alleles 130 repeats) and of SCA2 (alleles 122 repeats) were significantly higher in Caucasians than in Japanese. The relative prevalences of MJD/SCA3, SCA6, and DRPLA were significantly higher in Japanese pedigrees (43%, 11%, and 20%, respectively) than in Caucasian pedigrees (30%, 5%, and 0%, respectively), corresponding to the observation that the frequencies of large ANs of MJD/SCA3 (127 repeats), SCA6 (113 repeats), and DRPLA (117 repeats) were significantly higher in Japanese than in Caucasians. The close correlations of the relative prevalences of the dominant SCAs with the distributions of large ANs strongly support the assumption that large ANs contribute to generation of expanded alleles (AEs) and the relative prevalences of the dominant SCAs.
European Journal of Human Genetics, 1999
Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease characterised by the association of cerebellar ataxia and, in most patients, progressive macular degeneration leading to loss of autonomy and blindness. The patients die after 5-30 years of evolution. The cause of the disease has been identified as a (CAG) n repeat expansion in the coding sequence of the SCA7 gene on chromosome 3p. De novo mutations occur on intermediate-sized alleles carrying from 28 to 35 CAG repeats. Neomutations explain the persistence of the disease in spite of the great instability of the repeat sequence which results in the appearance of juvenile onset patients and the extinction of the disease within families. This rare disorder has been reported in a wide variety of countries and ethnic groups. In a large number of SCA7 families (n = 41) of different origins, we have determined the haplotypes segregating with the mutation of several microsatellite markers close to the SCA7 gene and of a new intragenic polymorphism (G 3145 TG/A 3145 TG). Four different haplotypes were found for centromeric markers (G 3145 TG/A 3145 TG-D3S1287-D3S3635) in the majority of the kindreds from four different geographic regions: A-2-4 in Korea; A-3-6 in North Africa, B-3-6 in continental Europe and A-4-6 in the UK and USA. The haplotypes in the Jamaican, Filipino, Brazilian and German families were different, suggesting that independent regional founders are at the origin of the SCA7 mutation in each population. Two different haplotypes were observed, however, in two families from the same rural area in central Italy in which de novo SCA7 mutations on intermediate alleles have been observed, suggesting the existence of different pools of at-risk chromosomes in this population.
Ancestral Origin of the ATTCT Repeat Expansion in Spinocerebellar Ataxia Type 10 (SCA10)
PLOS One, 2009
Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disease characterized by cerebellar ataxia and seizures. The disease is caused by a large ATTCT repeat expansion in the ATXN10 gene. The first families reported with SCA10 were of Mexican origin, but the disease was soon after described in Brazilian families of mixed Portuguese and Amerindian ancestry. The origin of the SCA10 expansion and a possible founder effect that would account for its geographical distribution have been the source of speculation over the last years. To unravel the mutational origin and spread of the SCA10 expansion, we performed an extensive haplotype study, using closely linked STR markers and intragenic SNPs, in families from Brazil and Mexico. Our results showed (1) a shared disease haplotype for all Brazilian and one of the Mexican families, and (2) closely-related haplotypes for the additional SCA10 Mexican families; (3) little or null genetic distance in small normal alleles of different repeat sizes, from the same SNP lineage, indicating that they are being originated by a single step mechanism; and (4) a shared haplotype for pure and interrupted expanded alleles, pointing to a gene conversion model for its generation. In conclusion, we show evidence for an ancestral common origin for SCA10 in Latin America, which might have arisen in an ancestral Amerindian population and later have been spread into the mixed populations of Mexico and Brazil.
Genetic polymorphism at spinocerebellar ataxia 1 and 2 loci in Brazil
Dynamic mutation involves the expansion of a tandem arrayed DNA sequence that is polymorphic in the population. This mechanism is associated with neurological/neuromuscular disorders and the pathology depends on the extension of the repeated tract, with a specific threshold for each disease. We made a PCR-based characterization of allelic polymorphism of SCA1 and SCA2 loci in a sample of 200 pairs of chromosomes in a population in Rio de Janeiro and found 23 different alleles at the SCA1 locus, varying from 10 to 39 CAG repeats (mean 27.7 ± 3.3, mode 28) and 10 different alleles ranging from 19 to 29 CAG (mean 22.1 ± 1.0, mode 22) at the SCA2 locus. The level of heterozygosis was 53% (SCA1) and 8% (SCA2).
Human Genetics, 2000
To identify various subtypes of spinocerebellar ataxias (SCAs) among 57 unrelated individuals clinically diagnosed as ataxia patients we analysed the SCA1, SCA2, SCA3, SCA6, SCA7 and DRPLA loci for expansion of CAG repeats. We detected CAG repeat expansion in 6 patients (10.5%) at the SCA1 locus. Ten of the 57 patients (17.5%) had CAG repeat expansion at the SCA2 locus, while four had CAG expansion at the SCA3/MJD locus (7%). At the SCA6 locus there was a single patient (1.8%) with 21 CAG repeats. We have not detected any patient with expansion in the SCA7 and DRPLA loci. To test whether the frequencies of the large normal alleles in SCA1, SCA2 and SCA6 loci can reflect some light on prevalence of the subtypes of SCAs we studied the CAG repeat variation in these loci in nine ethnic sub-populations of eastern India from which the patients originated. We report here that the frequency of large normal alleles (>31 CAG repeats) in SCA1 locus to be 0.211 of 394 chromosomes studied. We also report that the frequency of large normal alleles (>22 CAG repeats) at the SCA2 locus is 0.038 while at the SCA6 locus frequency of large normal alleles (>13 repeats) is 0.032. We discussed our data in light of the distribution of normal alleles and prevalence of SCAs in the Japanese and white populations.
De Novo Expansion of Intermediate Alleles in Spinocerebellar Ataxia 7
Human Molecular Genetics, 1998
Spinocerebellar ataxia 7 (SCA7) is the eighth neurodegenerative disorder caused by a translated CAG repeat expansion. Normal SCA7 alleles carry from four to 35 CAG repeats, whereas pathological alleles carry from 37 to ∼200. Intermediate alleles (IAs), with 28-35 repeats in the SCA7 gene are exceedingly rare in the general population and are not associated with the SCA7 phenotype, although they have been found among relatives of four SCA7 families. In two of these families, IAs bearing 35 and 28 CAG repeats gave rise, during paternal transmission, to SCA7 expansions of 57 and 47 repeats, respectively, that were confirmed by haplotype reconstructions in one case and by inference in the other. Furthermore, the four haplotypes segregating with IAs were identical to the expanded alleles in each kindred, but differed among the families, indicating multiple origins of the SCA7 mutation in these families with different geographical origins. Our results provide the first evidence of de novo SCA7 expansions from IAs that are not associated with the phenotype but can expand to the pathological range during some paternal transmissions. IAs that segregate in unaffected branches of the pedigrees might, therefore, constitute a reservoir for future de novo mutations that occur in a recurrent but random manner. This would explain the persistence of the disease in spite of the great anticipation (∼20 years/generation) characteristic of SCA7. So far, de novo expansions among the disorders caused by polyglutamine repeats have only been demonstrated in Huntington's disease.
Journal of Human Genetics, 2005
Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant cerebellar ataxia caused by CAG repeat expansion. We found expansion at SCA7 locus in only two out of 235 Indian families clinically diagnosed for ataxia. In one of the families, a de novo mutation was observed wherein a paternal allele in intermediate range of 31 CAG repeats expanded to 59 in the offspring leading to the disease. No expanded alleles were observed in the sperm of the transmitting parent by small pool PCR. This suggests that de novo expansion by a pre-zygotic event is unlikely and could be post-zygotic. SCA7 expanded alleles from the two families were present on different genetic backgrounds, indicating multiple origins of the mutation.
Spinocerebellar ataxias: microsatellite and allele frequency in unaffected and affected individuals
Arquivos de Neuro-Psiquiatria, 2009
The diagnosis and incidence of spinocerebelar ataxias (SCA) is sometimes difficult to analyze due the overlap of phenotypes subtypes and are disorders of mutations caused by CAG trinucleotide repeat expansion. To investigate the incidence of the SCA in Southern Brazil, we analyzed the trinucleotide repeats (CAG)n at the SCA1, SCA2, SCA3, SCA6 and SCA7 loci to identify allele size ranges and frequencies. We examined blood sample from 154 asymptomatic blood donors and 115 individuals with progressive ataxias.