Close Associations between Prevalences of Dominantly Inherited Spinocerebellar Ataxias with CAG-Repeat Expansions and Frequencies of Large Normal CAG Alleles in Japanese and Caucasian Populations

Abstract

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 dentatorubral-pallidoluysian 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 >30 repeats) and of SCA2 (alleles >22 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 (>27 repeats), SCA6 (>13 repeats), and DRPLA (>17 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.

Regional features of autosomal-dominant cerebellar ataxia in Nagano: clinical and molecular genetic analysis of 86 families

“…Compared with the averaged frequency of ADCA subtypes in other districts of Japan (Table 1) (Takano et al 1998;Sasaki et al 2003), the low frequency of SCA3/MJD is characteristic of Nagano. SCA3/MJD is the most prevalent ADCA subtype in Japan (Table 1) as well as in the majority of countries (Jardim et al 2001;Tang et al 2000;Stevanin et al 1997;van de Warrenburg et al 2002;Silveira et al 1998;Soong et al 2001).…”

Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia

“…This substitution was also found in other cohorts of Japanese families with ataxia (Ouyang et al 2006;Onodera et al 2006), while it was not found in Caucasian patients in Europe (Wieczorek et al 2006). The frequency of 16q-ADCA is considered to be relatively high in Japan, counted as the third or fourth major subtype of ADCA after MJD, SCA6, and DRPLA (Takano et al 1998;Sasaki et al 2003;Ohata et al 2006).…”

Spinocerebellar ataxias: microsatellite and allele frequency in unaffected and affected individuals

“…Molecular analysis of unrelated Brazilian families with SCA3 showed that normal alleles ranged from 12 to 33 (CAG)n 34 , and in other populations studied the two major alleles had 14 and 23 (CAG)n 13,35 . Comparisons of allelic frequencies must be made using population studies based on the CE methodology.…”

“…There are studies of clinically normal individuals with MJD in different populations that support the idea that the presence of alleles of size greater than or equal to 27 (CAG)n correlates with higher prevalence of MJD in patients 35 . According to this study we found alleles with a size equal to or greater than 27 (CAG)n in the MJD gene, and MJD is the most frequent ataxia among patients.…”