Polyglutamine tracts: no evidence of a major role in bipolar disorder

Turecki, Gustavo; Alda, Martin; Grof, Paul; Joober, Ridha; Cavazzoni, Patrizia; Duffy, Anne; Grof, Eva; Ahrens, B.; Berghöfer, Anne; Müller‐Oerlinghausen, B.; Dvořáková, M; Libigerová, E; Vojtechovsky, M; Zvolský, P; Nilsson, Agneta; Prochazka, Helena; Licht, Rasmus Wentzer; Rasmussen, N. A.; Schou, Mogens; Vestergaard, Per; Holzinger, Anita; Schumann, Claudia; Thau, K.; Rouleau, Guy A.

doi:10.1038/sj.mp.4000539

Cited by 14 publications

(5 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Schurhoff et al [1997] were unable to detect proteins with expanded polyglutamine in a sample of early onset schizophrenia (n ‫ס‬ 3) and bipolar disorder (n ‫ס‬ 4). Similarly, Jones et al [1997] found no expanded polyglutamine proteins associated with schizophrenia (n ‫ס‬ 18) or bipolar disorder patients (n ‫ס‬ 18), and Turecki et al [1999] found no different polyglutamine bands in 70 bipolar patients and 73 controls. Several more re-…”

Section: Polyglutamine-containing Protein Detectionmentioning

confidence: 91%

The unstable trinucleotide repeat story of major psychosis

et al. 2000

View full text Add to dashboard Cite

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...

show abstract

Section: Polyglutamine-containing Protein Detectionmentioning

confidence: 91%

The unstable trinucleotide repeat story of major psychosis

et al. 2000

View full text Add to dashboard Cite

show abstract

“…In addition, no evidence for polyglutamine tracts has been found in lymphoblastoid cell lines from BP patients [83]. Chandy et al [84] found a trend to increased repeat size in the hSKCa3 potassium channel gene in BP patients, but this was not replicated by Guy et al [85] in a case-control series, nor by McInnis et al [86•] in triads from the Hopkins pedigree series.…”

Section: Expanded Trinucleotide Repeatsmentioning

confidence: 93%

Genetics of bipolar affective disorder

Nürnberger

Foroud

2000

Curr Psychiatry Rep

View full text Add to dashboard Cite

Bipolar affective disorder is a highly heritable condition, as demonstrated in twin, family, and adoption studies. Morbid risk in first degree relatives is four to six times higher than the population prevalence of about 1%. However, the mode of inheritance is complex, and linkage findings have been difficult to replicate. Despite these limitations, consistent linkage findings have emerged on several chromosomes, notably 18p, 18q, 21q, 12q, 4p, and Xq. Two additional areas, 10p and 13q, have shown linkage in regions that appear to overlap with significant linkage findings in schizophrenia. Separate linkage studies in schizophrenia also have targeted the replicated bipolar linkages on 18p and 22q. New methods are being developed for fine mapping and candidate identification. Recent candidate gene studies include some positive results for the serotonin transporter gene on 17q and the catechol-o-methyltransferase gene on 22q. No other candidate gene studies are yet showing replicated results. A convincing demonstration for a susceptibility gene will probably require a mixture of case- control studies, family-based association methods, and pathophysiologic studies.

show abstract

“…If expanded CAG repeats are involved in the pathogenesis of BPD, large polyglutamine sequences may be evident in protein extracts from tissues obtained from BPD. Four studies have addressed this, but none have identified the postulated large polyglutamine repeats [Jones et al, 1997;Zander et al, 1998;Schurhoff et al, 1997;Turecki et al, 1999]. In myotonic dystrophy, and also possibly SCA8, the pathogenic repeat is an untranslated CTG, so these data do not allow full rejection of the hypothesis that CAG/CTG repeats are involved in BPD.…”

Section: Search For Polyglutamine Sequencesmentioning

confidence: 87%

Anticipation and repeat expansion in bipolar disorder

O’Donovan

Jones²,

Craddock³

2003

American J of Med Genetics Pt C

View full text Add to dashboard Cite

Anticipation is the phenomenon whereby a disease becomes more severe and/or presents with earlier onset as it is transmitted down through generations of a family. The only known mechanism for true anticipation is a class of mutations containing repetitive sequences exemplified by the pathogenic trinucleotide repeat. Studies of bipolar disorder (BPD) are consistent with the presence of anticipation and, by inference, the possibility that trinucleotide repeats contribute to this disorder, although it is possible that these data are the result of methodological problems. On the assumption that anticipation in BPD may be real, several surveys of the genome of BPD probands for large trinucleotide repeats have been conducted, as have studies of many repeat-containing candidate genes. No pathogenic triplet repeat has yet been unambiguously implicated.

show abstract

Polyglutamine tracts: no evidence of a major role in bipolar disorder

Cited by 14 publications

References 6 publications

The unstable trinucleotide repeat story of major psychosis

The unstable trinucleotide repeat story of major psychosis

Genetics of bipolar affective disorder

Anticipation and repeat expansion in bipolar disorder

Contact Info

Product

Resources

About