NOVEL MUTATIONAL MECHANISM IN MAN - EXPAN SION OF TRINUCLEOTIDE REPEATS

An analysis of a novel, recently discovered class of mutations in man - an expansion, i.e., an increase of the copy number of intragenic uns table trinucleotide repeats - is presented. The expansion of trinucleo tide repeats causes the development of at least seven hereditary disea ses which damage the nervous system: the fragile X chromosome syndrome (two separate variants of the disease - FRAXA and FRAXE), myotonic dy strophy, spinal and bulbar Kennedy's amyotrophy, Huntington's chorea, type 1, spinocerebellar ataxia, and dentatorubral-pallidolyusian atrop hy. The discovery of triplet expansion allows a satisfactory explanati on on the molecular level of a series of unusual clinical genetic phen omena, such as anticipation, the ''paternal transmission'' effect, the ''Sherman paradox'', and others. The common properties and the distin ctions of unstable trinucleotide mutations in the above-mentioned noso logic forms are analyzed comprehensively among for the mechanism by wh ich these mutations cause disease, the time of their appearance in ont ogenesis, and various clinical genetic correlations. The evolutionary origin of this class of mutations and, in particular, the role of alle les with an ''intermediate'' triplet number, which are the persistent reservoir of mutations arising de novo in a population, are also discu ssed. The possible implication of unstable trinucleotide repeats for a series of other hereditary diseases, such as spinocerebellar ataxia o f type 2, Machado-Joseph disease, hereditary spastic paraplegia, essen tial tremor, schizophrenia and others, is also suggested.