Beyond CAG Repeats: The Multifaceted Role of Genetics in Huntington Disease

被引:5
|
作者
Pengo, Marta [1 ]
Squitieri, Ferdinando [2 ,3 ]
机构
[1] Univ Brescia, Dept Mol & Translat Med, I-25121 Brescia, Italy
[2] Fdn Lega Italiana Ric Huntington LIRH, Ctr Neurol Rare Dis CMNR, I-00161 Rome, Italy
[3] IRCCS Casa Sollievo Sofferenza, Huntington & Rare Dis Unit, I-71013 San Giovanni Rotondo, Italy
关键词
gene modifiers; DNA mismatch repair; loss of interruption; somatic mutations; somatic instability; RNA toxicity; mtDNA; epigenetics; MITOCHONDRIAL-DNA DAMAGE; TRINUCLEOTIDE-REPEAT; MISMATCH REPAIR; RAN TRANSLATION; CTG REPEAT; EXPANSION; AGE; INSTABILITY; ONSET; POLYGLUTAMINE;
D O I
10.3390/genes15060807
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG expansion on the huntingtin (HTT) gene and is characterized by progressive motor, cognitive, and neuropsychiatric decline. Recently, new genetic factors besides CAG repeats have been implicated in the disease pathogenesis. Most genetic modifiers are involved in DNA repair pathways and, as the cause of the loss of CAA interruption in the HTT gene, they exert their main influence through somatic expansion. However, this mechanism might not be the only driver of HD pathogenesis, and future studies are warranted in this field. The aim of the present review is to dissect the many faces of genetics in HD pathogenesis, from cis- and trans-acting genetic modifiers to RNA toxicity, mitochondrial DNA mutations, and epigenetics factors. Exploring genetic modifiers of HD onset and progression appears crucial to elucidate not only disease pathogenesis, but also to improve disease prediction and prevention, develop biomarkers of disease progression and response to therapies, and recognize new therapeutic opportunities. Since the same genetic mechanisms are also described in other repeat expansion diseases, their implications might encompass the whole spectrum of these disorders.
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页数:15
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