Genes with triplet repeats: candidate mediators of neuropsychiatric disorders

doi:10.1016/0166-2236(93)90175-L

Trends in Neurosciences

Volume 16, Issue 7, July 1993, Pages 254-260

https://doi.org/10.1016/0166-2236(93)90175-L Get rights and content

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, spino-cerebellar 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.

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All of them were not reported in the dbSNP database, and some of them were inherited from unaffected parents after analysis of available parents’ DNA. The exon1 of neurexin-1β contains CG-rich sequences, therefore it is hypothesized that variation in the length of CCG, CGC, GCC, CGG, GCG, and GGC repeats (collectively referred to as CCG repeats) might contribute to a number of neuropsychiatric disorders such as bipolar affective disorder, schizophrenia, and autism (Margolis et al., 1999; Ross, 1997; Ross et al., 1998; Ross et al., 1993). Interestingly, we identified similar variants in eight control subjects (Table 2), consistent with the length polymorphism of trinucleotide repeats and other units of unstable DNA (Riggins et al., 1992; Sasaki et al., 1996).
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Recent studies have shown that gene mutations are involved in the pathology of neurological disorders. CCG repeats cause genetic instability and are localized at the 5′ end of the non-coding regions of the FMR1 gene in fragile X syndrome. Our studies for the first time showed that aluminum (Al) levels were elevated in the serum samples of fragile X syndrome and also provide evidence for the interaction of aluminum with (CCG)₁₂-repeats. Circular dichroism spectroscopic studies of (CCG)₁₂ indicated B-DNA conformation and in the presence of Al (10⁻⁵ M) CCG repeats attained Z-DNA conformation. Further spectroscopic studies, which included melting profiles, ethidium bromide binding patterns and interaction of Z-DNA specific polyclonal antibodies confirmed the Z-conformation in (CCG)₁₂-repeats in the presence of Al (10⁻⁵ M). It is interesting to mention that Al-induced Z-conformation is stable even after the total removal of Al from CCG by desferoximine, a chelating drug. This is the first report to proof the role of Al in modulating the DNA (CCG repeats) topology and this information provides a clue about the possible involvement of Al at a molecular level in neurological/neurodegenerative disorders.

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Trends in Neurosciences

Perspective on diseaseGenes with triplet repeats: candidate mediators of neuropsychiatric disorders

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Perspective on disease
Genes with triplet repeats: candidate mediators of neuropsychiatric disorders