The unstable trinucleotide repeat story of major psychosis

Abstract

New hopes for cloning susceptibility genes for schizophrenia and bipolar affective disorder followed the discovery of a novel type of DNA mutation, namely unstable DNA. One class of unstable DNA, trinucleotide repeat expansion, is the causal mutation in myotonic dystrophy, fragile X mental retardation, Huntington disease and a number of other rare Mendelian neurological disorders. This finding has led researchers in psychiatric genetics to search for unstable DNA sites as susceptibility factors for schizophrenia and bipolar affective disorder. Increased severity and decreased age at onset of disease in successive generations, known as genetic anticipation, was reported for undifferentiated psychiatric diseases and for myotonic dystrophy early in the twentieth century, but was initially dismissed as the consequence of ascertainment bias. Because unstable DNA was demonstrated to be a molecular substrate for genetic anticipation in the majority of trinucleotide repeat diseases including myotonic dystrophy, many recent studies looking for genetic anticipation have been performed for schizophrenia and bipolar affective disorder with surprisingly consistent positive results. These studies are reviewed, with particular emphasis placed on relevant sampling and statistical considerations, and concerns are raised regarding the interpretation of such studies. In parallel, molecular genetic investigations looking for evidence of trinucleotide repeat expansion in both schizophrenia and bipolar disorder are reviewed. Initial studies of genome-wide trinucleotide repeats using the repeat expansion detection technique suggested possible association of large CAG/CTG repeat tracts with schizophrenia and bipolar affective disorder. More recently, three loci have been identified that contain large, unstable CAG/CTG repeats that occur frequently in the population and seem to account for the majority of large products identified using the repeat expansion detection method. These repeats localize to an intron in transcription factor gene SEF2-1B at 18q21, a site named ERDA1 on 17q21 with no associated coding region, and the 3' end of a gene on 13q21, SCA8, that is believed to be responsible for a form of spinocerebellar ataxia. At present no strong evidence exists that large repeat alleles at either SEF2-1B or ERDA1 are involved in the etiology of schizophrenia or bipolar disorder. Preliminary evidence suggests that large repeat alleles at SCA8 that are non-penetrant for ataxia may be a susceptibility factor for major psychosis. A fourth, but much more infrequently unstable CAG/CTG repeat has been identified within the 5' untranslated region of the gene, MAB21L1, on 13q13. A fifth CAG/CTG repeat locus has been identified within the coding region of an ion transporter, KCNN3 (hSKCa3), on 1q21. Although neither large alleles nor instability have been observed at KCNN3, this repeat locus has been extensively analyzed in association and family studies of major psychosis, with conflicting findings. Studies of polyglutamine containing genes i...

Association of CAG repeat loci on chromosome 22 with schizophrenia and bipolar disorder

“…This makes them ideal candidate genes for schizophrenia and bipolar disorder as expanded glutamine repeats have been associated with neuro-degenerative disorders and novel proteins with expanded polyglutamine tracts have been identified in patients with schizophrenia. 16,33 All the loci we have studied were polymorphic although the heterozygosity is not as high as that seen in most of the diseases associated with unstable trinucleotide repeats. 34 We were unable to observe any large-scale expansion in the patients as compared to the normals.…”

“…16 To date, more than a dozen neurological disorders have been shown to be caused by trinucleotide repeat expansions with the CAG repeat being the most frequently involved triplet. When the CAG triplet occurs in the coding regions, expansion results in long polyglutamine stretches which are thought to mediate the disease process.…”

“…[17][18][19] One of the most important features common to these diseases and bipolar disorder and schizophrenia is the phenomenon of anticipation. 16,20,21 This inheritance pattern refers to the increase in disease severity with a reduction in the age at onset when the disease is transmitted in successive generations. The molecular basis for anticipation was elucidated with the discovery of trinucleotide repeat expansions where the increase of repeat number during intergenerational transmission results in the increased disease severity and a reduced age at onset.…”

“…The candidate gene approach however, has been unable to demonstrate large expansions of trinucleotide repeats in the range of those seen in the diseases caused by triplet repeat expansions in patients suffering from schizophrenia and bipolar disorder. 16 The failure to observe large expansions has led to suggestions that it might be worthwhile studying moderate trinucleotide repeat expansions in patients suffering from these diseases. 25 We have also earlier proposed that a difference in allele sizes or 'allele span' at such polymorphic trinucleotide repeat loci may also be implicated in bipolar disorder and schizophrenia.…”

Alu in Lynch Syndrome: A Danger SINE?

“…P erez-Cabornero and colleagues raise the issue of anticipation in kindreds carrying the MSH2 exons 4 to 8 deletion, because disease severity in terms of cancer number, spectrum, and age of onset seemed to worsen with each successive generation. The phenomenon of anticipation, whereby the symptoms of a disease arise at a younger age and show increased severity in later generations, is exemplified by disorders associated with triplet repeat expansion such as myotonic dystrophy (31). Although initially dismissed as a consequence of ascertainment bias, this phenomenon now has a well-established molecular basis as the continued expansion in copy number of these unstable repeats during gametogenesis, with the phenotypic severity in offspring correlating with repeat length (31).…”