Spinocerebellar ataxia type 1 (SCA1): Phenotype-genotype correlation studies in intermediate alleles

Abstract

CAG repeat expansions with loss of CAT interruptions in the coding region of the ataxin-1 gene are associated with spinocerebellar ataxia type 1 (SCA1). For molecular genetic diagnosis it is necessary to define the limits of normal and pathological size ranges. In most studies, normal alleles as measured by PCR range from 6 ± 39 units with interruptions of 1 ± 3 CAT trinucleotides that are thought to be involved in the stability of the trinucleotide stretch during DNA replication. Expanded alleles have been reported to carry 39 ± 81 CAG trinucleotides without stabilising CAT interruptions. To evaluate the limits between normal and disease size ranges we analysed the repeat length and composition of the SCA1 gene in 15 individuals with alleles ranging from 36 and 41 triplets for genotype-phenotype correlation studies. We found the 39 trinucleotide-allele to be either interrupted by CAT repeats or formed by a pure CAG stretch. The clinical features of individuals carrying 39 uninterrupted CAG repeats did not differ from the SCA1 phenotype in general with dysphagia, pale discs, pyramidal signs and cerebellar tremor being more frequent as compared to other SCA genotypes. In contrast, the interrupted 39 trinucleotide-allele is not correlated with the SCA1 phenotype.

Direct and accurate measurement of CAG repeat configuration in the ataxin-1 (ATXN-1) gene by “dual-fluorescence labeled PCR-restriction fragment length analysis”

“…Sobczak and Krzyzosiak (2004) developed a new method, ''SSCP-duplex analysis'', and showed exact CAG repeat configurations in 50 Polish individuals. Hellenbroich and his colleague developed a method that would detect actual CAG repeat by using non-labeled primers and SfaNI digestion (Zhulke et al 2002). They studied in their German population and found rare alleles with mild CAG repeat expansion.…”

“…C The distribution of actual (pure) CAG repeat number encoding polyglutamine in the region 3 0 (downstream) of the last CAT interruption. Pure CAG repeat in the 3 0 -region ranges from 7 to 23 repeat-units, and two major peaks are seen at 10 and 16 CAG repeats allowed one to measure total CAG and CAT repeat-units (Goldfarb et al 1996;Jodice et al 1997;Matsuyama et al 1999;Pujana et al 1999;Zhulke et al 2002). Sobczak and Krzyzosiak (2004) developed a new method, ''SSCP-duplex analysis'', and showed exact CAG repeat configurations in 50 Polish individuals.…”

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

“…When the mean allelic size of patients was compared with normal asymptomatic population we found a significant difference in the SCA2 and SCA3 (Table 10). The 36-repeat allele in the SCA1 locus is borderline in some populations being an intermediate allele with reduced penetrance 8 . Therefore, patients who have this allele should be considered negative for SCA1 in southern Brazilian population.…”

“…Our data found no intermediate alleles for SCA2, SCA3, SCA6 or SCA7 in the unaffected population. However, studies of families with SCA traits usually reveal an intermediate allele size 3,8,10,33 . Probably, intermediate alleles are as rare as the expanded alleles and it must be found only in affected families with the disease.…”

“…The number of CAG trinucleotide repeats varies from one population to another [2][3][4] . In normal individuals, SCA 1 alleles range from 6 to 39 CAG repeats (CAGn) [5][6][7][8] ; in SCA2 alleles range from 15 to 24 CAGn 9-11 ; in SCA3 (Machado Joseph disease -MJD) from 13 to 41 CAGn [12][13][14] ; in SCA6¨from 6 to 16 CAGn [15][16] , and in SCA7 ranges from 4 to 17 CAGn [17][18] . Intermediate alleles are found in studies with families which have not been described in the normal population.…”