Spinocerebellar ataxia type 8: Molecular genetic comparisons and haplotype analysis of 37 families with ataxia
Spinocerebellar ataxia type 8: Molecular genetic comparisons and haplotype analysis of 37 families with ataxia
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DOI：
10.1086/422014
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发表时间：
2004-07-01
影响因子：
9.8
通讯作者：
Ranum, LPW
中科院分区：
文献类型：
--
作者：
Ikeda, Y;Dalton, JC;Ranum, LPW
我们在其他地方报道了一个未翻译的CTG扩增导致显性遗传性神经退行性疾病脊髓小脑共济失调8型（SCA8）。SCA8显示了一种复杂的遗传模式，具有极端的不完全遗传，在一个给定的家庭中通常只有一个或两个受影响的个体。在对照染色体中也发现了SCA 8扩展，这表明单独的遗传或环境因素增加了携带SCA 8扩展的共济失调患者的疾病外显率。我们描述了来自美国、加拿大、日本和墨西哥的37个不同SCA8共济失调家族的分子遗传学特征和疾病发病率。应用17个STR标记对共济失调家系、普通人群中的一组CTG扩增携带者和精神病患者进行单倍型分析，以阐明CTG扩增率降低的遗传基础，并探讨不同人群中CTG扩增是否具有共同的祖先背景。在患有共济失调的白色家庭、正常对照和严重精神病患者中发现了两种主要的祖先相关单倍型（A和A '），表明白人中致病性和非致病性SCA 8扩展有共同的祖先起源。另外两个不同的单倍型被发现在一组日本家庭与共济失调（单倍型B）和一个墨西哥家庭与共济失调（单倍型C）。我们的研究发现，SCA8扩增的三个独立产生的单倍型中发现共济失调患者和共分离与共济失调时，多个家庭成员受到影响，进一步支持的CTG扩展在疾病的发病机制中的直接作用。
We reported elsewhere that an untranslated CTG expansion causes the dominantly inherited neurodegenerative disorder spinocerebellar ataxia type 8 (SCA8). SCA8 shows a complex inheritance pattern with extremes of incomplete penetrance, in which often only one or two affected individuals are found in a given family. SCA8 expansions have also been found in control chromosomes, indicating that separate genetic or environmental factors increase disease penetrance among SCA8-expansion-carrying patients with ataxia. We describe the molecular genetic features and disease penetrance of 37 different families with SCA8 ataxia from the United States, Canada, Japan, and Mexico. Haplotype analysis using 17 STR markers spanning an similar to1-Mb region was performed on the families with ataxia, on a group of expansion carriers in the general population, and on psychiatric patients, to clarify the genetic basis of the reduced penetrance and to investigate whether CTG expansions among different populations share a common ancestral background. Two major ancestrally related haplotypes (A and A') were found among white families with ataxia, normal controls, and patients with major psychosis, indicating a common ancestral origin of both pathogenic and nonpathogenic SCA8 expansions among whites. Two additional and distinct haplotypes were found among a group of Japanese families with ataxia (haplotype B) and a Mexican family with ataxia ( haplotype C). Our finding that SCA8 expansions on three independently arising haplotypes are found among patients with ataxia and cosegregate with ataxia when multiple family members are affected further supports the direct role of the CTG expansion in disease pathogenesis.