Genes with triplet repeats: candidate mediators of neuropsychiatric disorders

Abstract

Recently a new form of human mutation-expansion of trinucleotide repeats-has been found to cause the diseases of fragile X syndrome, spinal and bulbar muscular atrophy, myotonic dystrophy and, most recently, Huntington's disease. We review the emerging data on the genetics and neurobiology of these disorders. Three are characterized by unusual patterns of inheritance, in particular, genetic 'anticipation', in which the severity of the disorder increases and the age of onset decreases in successive generations of a pedigree. Several idiopathic neuropsychiatric disorders have features of inheritance consistent with anticipation. In bipolar affective disorder, there is evidence for both earlier age of onset and more severe illness in the second generation of a subset of unilineal pedigrees. There is also the suggestion of anticipation in some forms of schizophrenia, spinocerebellar atrophy and autism. Triplet repeats are present in additional known genes, both in coding regions and untranslated regions. Furthermore, many novel genes with triplet repeats are expressed in the human brain, and these are candidates to cause some forms of these neuropsychiatric disorders.