1型脊髓小脑共济失调中存在导致代际CAG重复序列不稳定的机制的证据。

Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I.

作者信息

Chung M Y, Ranum L P, Duvick L A, Servadio A, Zoghbi H Y, Orr H T

机构信息

Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455.

出版信息

Nat Genet. 1993 Nov;5(3):254-8. doi: 10.1038/ng1193-254.

DOI:10.1038/ng1193-254

PMID:8275090

Abstract

Spinocerebellar ataxia type I (SCAI) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat on chromosome 6p. Normal alleles range from 19-36 repeats while SCA1 alleles contain 43-81 repeats. We now show that in 63% of paternal transmissions, an increase in repeat number is observed, whereas 69% of maternal transmissions showed no change or a decrease in repeat number. Sequence analysis of the repeat from 126 chromosomes reveals an interrupted repeat configuration in 98% of the unexpanded alleles but a contiguous repeat (CAG)n configuration in 30 expanded alleles from seven SCA1 families. This indicates that the repeat instability in SCA1 is more complex than a simple variation in repeat number and that the loss of an interruption predisposes the SCA1 (CAG)n to expansion.

摘要

I型脊髓小脑共济失调（SCAI）是一种常染色体显性神经退行性疾病，由6号染色体短臂上CAG三核苷酸重复序列的扩增引起。正常等位基因的重复次数为19 - 36次，而SCA1等位基因的重复次数为43 - 81次。我们现在发现，在63%的父系遗传中，观察到重复次数增加，而69%的母系遗传显示重复次数没有变化或减少。对126条染色体上的重复序列进行序列分析发现，在98%未扩增的等位基因中，重复序列呈间断结构，但在来自7个SCA1家族的30个扩增等位基因中，重复序列呈连续的（CAG）n结构。这表明SCA1中的重复序列不稳定性比简单的重复次数变化更为复杂，并且间断结构的缺失使SCA1（CAG）n易于扩增。