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Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis.

Abstract：

:Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Although the mutant protein is widely expressed, the earliest and most striking neuropathological changes are observed in the striatum. Here we show dramatic mutation length increases (gains of up to 1000 CAG repeats) in human striatal cells early in the disease course, most likely before the onset of pathological cell loss. Studies of knock-in HD mouse models indicate that the size of the initial CAG repeat mutation may influence both onset and tissue-specific patterns of age-dependent, expansion-biased mutation length variability. Given that CAG repeat length strongly correlates with clinical severity, we suggest that somatic increases of mutation length may play a major role in the progressive nature and cell-selective aspects of both adult-onset and juvenile-onset HD pathogenesis and we discuss the implications of this interpretation of the data presented.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Kennedy L,Evans E,Chen CM,Craven L,Detloff PJ,Ennis M,Shelbourne PF

doi

10.1093/hmg/ddg352

subject

Has Abstract

pub_date

2003-12-15 00:00:00

pages

3359-67

issue

24

eissn

0964-6906

issn

1460-2083

pii

ddg352

journal_volume

12

pub_type

杂志文章

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