Regional distribution of polymorphisms associated to the disease-causing gene of spinocerebellar ataxia type 3

Abstract

Introduction: Knowledge about the distribution and frequency of the respective haplotypes on the wildtype and mutant allele is highly relevant in the context of future gene therapy clinical studies in Spinocerebellar Ataxia Type 3, the most common autosomal dominantly inherited ataxia. Single nucleotide polymorphisms associated to the disease-causing gene, ATXN3, have been determined. We wanted to investigate the frequency and regional distribution of two intragenic single nucleotide polymorphisms (SNPs) in a large European SCA3 cohort and their relation to the clinical phenotype.

Methods: The genotypes of the two polymorphisms at base pair positions 987 and 1118 of the ATXN3 were determined for their co-localization on the normal and expanded allele, respectively, in 286 SCA3 mutation carriers and 117 healthy controls from 11 European sites.

Results: The distribution of genotypes on the expanded allele differed from those of the wildtype allele of SCA3 mutation carriers and of healthy controls, and was mainly influenced by the regional origin. In our cohort, no particular clinical phenotype was associated with any specific haplotype.

Conclusions: Our results confirm distinct allocations of SNPs associated to the expanded ATXN3, and accordingly the consideration of allele-specific therapies.

Keywords: ATXN3; ASO; Polymorphism; SCA3; SNP; Spinocerebellar ataxia.

Fig. 1

Relative frequencies of the SNP distributions at bp987 and bp1118 on the wildtype and expanded alleles. The relative frequencies of Guanine (green) and Cytosine (blue) at bp987 (A) and of Adenine (red) and Cytosine (blue) at bp1118 (B) are given for healthy controls as well as the wildtype and expanded allele in SCA3 mutation carriers, respectively. In the box on the far left, the distribution of the extended allele is further categorised: The respective proportion in which the wildtype and the expanded allele do not differ, e.g. do have the same nucleobase, is hatched. The distribution in controls is comparable to those of the wildtype allele in SCA3, while both are significantly different from the distribution on the expanded allele of SCA3 (p < 0.001)

Fig. 2

Relative frequencies of the SNPs at bp987 (A) and bp1118 (B) of the wildtype and expanded allele for each European site. Color codes the nucleobase at the expanded allele: cytosine in blue, guanine in green and adenine in red. Full-colored areas indicate the proportion with a different nucleobase at wildtype and expanded allele, while the hatched areas indicate the presence of the same nucleobase at wildtype and expanded allele

Fig. 3

Relative frequencies of the haplotypes of the wildtype and expanded allele at bp987 and bp1118 for SCA3 mutation carriers. Blue areas represent the frequency of Cytosine (bp987)–Adenine (bp1118), green areas the frequency of Cytosine–Cytosine, ochre areas the frequency of Guanine–Adenine and purple areas the frequency of Guanine–Cytosine, respectively

Fig. 4

Relative frequencies of neurological, non-ataxia signs. The relative frequencies of additional neurological signs other than ataxia are given for the four haplotypes of the expanded allele (bp987 and bp1118) respectively: Guanine–Cytosine (G–C, N = 54), Guanine–Adenine (G–A, N = 10), Cytosine–Cytosine (C–C, N = 12) and Cytosine–Adenine (C–A, N = 150). Bars indicating the presence of each item are colored in green, and the remaining proportion with absence of the respective sign is marked in blue

Fig. 5

Relative frequencies of haplotypes at SNP bp987–bp1118 on the expanded allele for each European site. The blue area represents the frequency of Cytosine (bp987) –Adenine (bp1118), the green area the frequency of Cytosine–Cytosine, the ochre area the frequency of Guanine–Adenine and the purple area the frequency of Guanine–Cytosine, respectively