Insights into the mutational history and prevalence of SCA1 in the Indian population through anchored polymorphisms

Abstract

There is a wide variation in prevalence of spinocerebellar ataxia type 1 (SCA1) in different populations. In the present study, we observed SCA1 in approximately 22% (37/167 families) of the autosomal dominant cerebellar ataxias (ADCAs) in the Indian population. We investigated the role of various genetic factors like repeat length, interruption pattern and chromosomal background in predisposing the repeats to instability in these families. We analyzed 12 markers (9 SNPs and 3 microsatellite markers) and found 3 of them, spanning a region of approximately 65 kbp to be linked with the disease locus in the Indian population. The haplotype C-4-C defined by rs1476464 (SNP9)-D6S288-rs2075974 (SNP1), which was extremely rare in nonaffected chromosomes (approximately 3%), was observed to be significantly (P<0.0000) associated with the expanded chromosomes in approximately 44% of SCA1 families. This haplotype was found in all nonhuman primates. SNP1 (C/T), which showed a skewed allelic distribution between large (LN > 30 repeats) and small normal (SN <or= 30 repeats) alleles (P<0.0000) had similar allelic distribution (P=0.3477) in LN and expanded alleles. Our study suggested that LN and expanded chromosomes linked with the ancestral C allele of SNP1 might have originated simultaneously during evolution by the lengthening of repeats. The LN alleles might have accumulated repeat stabilizing non-CAG interruptions during this process. Similar proportions of T allele in SN with single interruptions, LN and expanded chromosomes lend credence to the origin of expanded alleles from singly-interrupted chromosomes. Our analyses using markers linked (anchoring) to SCA1 suggest that prevalence of SCA1 is correlated to both repeat length and number of interruptions in the Indian population. The spectrum of these alleles also points toward the antiquity of SCA1 mutation in the Indian population.

SCA-LSVD: A repeat-oriented locus-specific variation database for genotype to phenotype correlations in spinocerebellar ataxias

“…Over the last 10 years our group has been involved in genetic studies of various hereditary ataxias and has built up the largest resource of ataxia in India. We have reported differences in their prevalence and have also identified founders for various SCAs in the Indian population [Bahl et al, 2005;Choudhry et al, 2001;Mittal et al, 2005aMittal et al, , 2005bPadiath et al, 2005;Srivastava et al, 2001]. All the ataxias are not prevalent in India (Fig.…”

“…The prevalence is probably accounted for by regional founder effects, as evidenced through linkage disequilibrium studies using flanking markers at various loci like SCA1, SCA2, SCA3, SCA6, SCA12, DRPLA, and FRAXA in different populations [Bahl et al, 2005;Basu et al, 2000;Chakravarty and Mukherjee, 2002;Choudhry et al, 2001;Cossee et al, 1997;Eichler et al, 1994;Gaspar et al, 2001;Imbert et al, 1996;Mittal et al, 2005aMittal et al, , 2005bRubinsztein et al, 1994;Saleem et al, 2000;Terasawa et al, 2004]. In a few ataxias, disease prevalence correlates with the frequency of repeats in the higher range of normal alleles (LNs) and occurrence of stabilizing interruptions in the repeat stretch [Cossee et al, 1997;Takano et al, 1998;Saleem et al, 2000;Mittal et al, 2005b].…”

“…All the ataxias are not prevalent in India (Fig. 1) and their frequencies vary across different ethnic populations of India [Basu et al, 2000;Krishna et al, 2007;Mittal et al, 2005b]. Keeping this objective in mind, we have built a locusspecific variation database (LSVD) for ataxia (named SCA-LSVD), which is specifically focused toward genes that have repeat involvement.…”

Spinocerebellar ataxia 1: case and cohort-based studies in India

“…However, in southern India, four independent studies point to a higher incidence of SCA1 over other SCAs 13,14,19,38 . When the frequencies of SCA1 patients from hospitals were compared amongst the ADCAs, they were twice in southern India (33%, 20/60 families) than in northern India (15%, 17/107 families) 13 .…”

“…Currently, no treatment is available either for curing SCA1 or delaying the onset of the disease 9 . Majority of SCA1 studies in India are hospital-based [10][11][12][13][14][15] and hence cross-sectional; thus they fail to reveal characteristic clinical features of disease progression. Specific cohortbased studies on the natural history and clinical characteristics of SCAs are gaining importance because such studies could help in understanding the preclinical stages of SCA, where therapy is likely to be most effective.…”