title: Triplet repeats, RNA secondary structure and toxic gain-of-function models for pathogenesis.
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.
authors.affiliation: Institute of Histology and Embryology, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: R
authors.initials: R
authors.lastname: Galvão
authors.forename: L
authors.initials: L
authors.lastname: Mendes-Soares
authors.forename: J
authors.initials: J
authors.lastname: Câmara
authors.forename: I
authors.initials: I
authors.lastname: Jaco
authors.forename: M
authors.initials: M
authors.lastname: Carmo-Fonseca
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D008969:Molecular Sequence Data; D009223:Myotonic Dystrophy / Q000209:etiology / Q000235:genetics*; D009690:Nucleic Acid Conformation; D010455:Peptides / Q000235:genetics; D039102:Poly(A)-Binding Proteins; D012313:RNA / Q000737:chemistry* / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000209:etiology / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D010455:Peptides; D039102:Poly(A)-Binding Proteins; D016601:RNA-Binding Proteins; C097188:polyglutamine; D012313:RNA