Unstable expansion of triplet repeats as a new disease mechanism for neurodegenerative diseases

Abstract

IntroductionNeurodegenerative diseases have been defined as diseases characterized by gradual loss of neurops in particular regions of the central nervous system due to "unknown" causes. Substantial number of neurodegenerative diseases exhibit familial occurrence, suggesting that mutations in the causative genes are the primary cause of the diseases. Application of the molecular genetic strategy of "positional cloning" has enabled us to identify the causative genes without prior knowledge of the pathophysiology of the diseases. Among the causative genes which have been identified by the strategy of positional cloning, unstable expansions of triplet repeats have recently been discovered to be a common novel disease mechanism for neurodegenerative diseases. In this review I will focus on recent developments in the research on triplet repeat diseases with particular emphasis on non-Mendelian aspects of triplet repeat diseases.

Sharing of polyglutamine localization by the neuronal nucleus and cytoplasm in CAG‐repeat diseases

“…The expansion of a CAG repeat encoding a polyglutamine tract is a common gene mutation in several hereditary neurodegenerative diseases, including Huntington's disease (HD), Machado-Joseph disease (MJD), and dentatorubral-pallidoluysian atrophy (DRPLA) [1,2]. The commonly observed formation of neuronal intranuclear inclusions (NIIs) in affected brain lesions in each disorder and the presence of causative gene products with expanded polyglutamine (polyQ) stretches in the inclusions suggest that NIIs are structures that are involved in the pathogenic mechanism underlying these disorders [3][4][5][6][7][8].…”

Population Genetics of Wild-Type CAG Repeats in the <i>Machado-Joseph Disease</i> Gene in Portugal

“…In expansion disorders a tendency for the expanded alleles to further increase in size in successive generations has been reported, particularly in male transmissions [23] . In MJD, few contractions have been described for the expanded trinucleotide repeats, and a bias in favor of expansions seems to exist [24] , although to a smaller degree than what is seen in Huntington disease (HD) [25] .…”

Human genetics: Past, present, and future, with special reference to major trends in Japan

“…The size of the repeats showed a close correlation with the age of onset and severity of the disease. The expansion of the triplet repeats accounted for a number of clinical characteristics such as the phenomenon of anticipation and a wide variety of clinical manifestations of the disease [182,183,186].…”