Abstract:
:Ten years after the discovery of human diseases caused by trinucleotide repeat expansions, searching for mechanistic links between gene mutation and pathological phenotype remains a fundamental and unsolved issue. Evidence accumulated so far indicates that the pathogenesis of repeat disorders is complex and multi-factorial. Diseases caused by CAG expansions coding for polyglutamine tracts have been extensively studied, and in most cases a toxic gain-of-function of the mutant protein was demonstrated. Most recently, tracking the effects of repeats along the pathway of gene expression is providing additional clues to understand how a triplet repeat expansion can cause disease. Expanded repeats form DNA secondary structures that confer genetic instability, and most likely contribute to alter the local chromatin configuration leading to transcriptional silencing. At the level of RNA, the expanded repeat may either interfere with processing of the primary transcript, resulting in deficit of the corresponding protein, or interact with RNA-binding proteins altering their normal activity. The latter mechanism, termed RNA gain-of-function, has no precedents in human genetics. Recent evidence suggests that expanded RNAs and associated RNA-binding proteins are potential contributors to the pathogenesis of several triplet repeat diseases.
journal_name
Brain Res Bulljournal_title
Brain research bulletinauthors
Galvão R,Mendes-Soares L,Câmara J,Jaco I,Carmo-Fonseca Mdoi
10.1016/s0361-9230(01)00651-7keywords:
subject
Has Abstractpub_date
2001-10-01 00:00:00pages
191-201issue
3-4eissn
0361-9230issn
1873-2747pii
S0361-9230(01)00651-7journal_volume
56pub_type
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journal_title:Brain research bulletin
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journal_title:Brain research bulletin
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