Analysis of the CAG repeats in the SCA1 and B37 genes in schizophrenic and bipolar I disorder patients: Tentative association between B37 and schizophrenia

Morris-Rosendahl, Deborah J.; Burgert, E. Omer; Uyanık, Gökhan; Mayerová, A; Duval, Fabrice; Macher, Jean-Paul; Crocq, Marc‐Antoine

doi:10.1002/(sici)1096-8628(19970531)74:3<324::aid-ajmg15>3.0.co;2-q

Cited by 13 publications

(9 citation statements)

References 45 publications

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“…As several studies have suggested an association between large CAG repeats and severe mental illnesses using the repeat expansion detection (RED) method, 15-17 the result is not unequivocal 18 and the candidate genes for schizophrenia remain unidentified. 19,20 The results of our study, nevertheless, exclude the possible involvement of the CAG triplet-containing gene, KCNN3, in the pathogenesis of schizophrenia in our population.…”

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confidence: 39%

Genetic association study of a polymorphic CAG repeats array of calcium-activated potassium channel (KCNN3) gene and schizophrenia among the Chinese population from Taiwan

et al. 1999

Mol Psychiatry

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Chandy et al suggested that a novel human neuronal small conductance, calcium-activated potassium channel gene, KCNN3, might be a candidate for schizophrenia. 1 The KCNN3 cDNA sequences contain two stretches of CAG trinucleotide repeats encoding two separate polyglutamine segments near the N-terminus of this channel protein. The second CAG repeat was found to be highly polymorphic in the Caucasian population from both Europe and USA. Upon comparing the allelic frequency distribution between schizophrenic patients and ethnically matched controls, a significant excess of longer CAG repeats in schizophrenic patients was observed. A similar result was obtained in a recent replication study by Bowen et al, 2 performed in Caucasians from UK or Eire. These results suggest an association between the longer CAG repeat allele of the KCNN3 gene and schizophrenia susceptibility. To verify if similar results can be observed in the Chinese population, we carried out a case-control study to compare the allelic frequency distribution of the CAG repeat of the KCNN3 gene between 92 Chinese schizophrenic patients and 100 normal controls from Taiwan. No significant difference of the allelic frequency distribution of the second CAG repeats was detected between the two groups (Wilcoxon Rank Sum test, P = 0.664). In addition, no over-representation of CAG repeats longer than the mode (19 repeats) was found in the patients' group (Fisher's exact test, P = 0.739). Thus, our data do not support that the second polymorphic CAG repeat of the KCNN3 gene may have an association with schizophrenia in our population.

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confidence: 39%

Genetic association study of a polymorphic CAG repeats array of calcium-activated potassium channel (KCNN3) gene and schizophrenia among the Chinese population from Taiwan

et al. 1999

Mol Psychiatry

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“…All patients and controls described here have previously been used in other published studies. 13,18 European patients: Unrelated patients of French or Alsatian ancestry meeting DSM-IV criteria for schizophrenia or BPD-I were genotyped; Mediterranean Caucasians, Asians, and Africans were excluded. Patients were examined with an unstructured clinical interview and also with a structured clinical interview (SADSLifetime Version, 35 final diagnoses being made by a consensus of two psychiatrists.…”

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confidence: 99%

“…[9][10][11][12] Despite extensive studies, the precise gene(s) containing the longer CAG alleles associated with neuropsychiatric disorders remain unidentified. [13][14][15] In this study, we describe a novel potassium channel gene, hSKCa3, involved in neuronal excitability, that shows the predicted signifi- ) is derived from a combination of the published AAD14 cDNA, our human genomic and brain cDNA sequences, and the human EST AA285078; rSKCa3 is derived from the published cDNA sequence. The putative transmembrane segments and pore region are bracketed, and the two polyglutamine arrays are shown in bold and bracketed.…”

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confidence: 99%

“…Using a microsatellite assay, we genotyped the second repeat in 319 chromosomes in unrelated Caucasian adult controls from Europe and USA. 13,18 Alleles ranged in length from 12 to 28 CAG repeats, the modal length being 19 repeats for both populations ( Figure 2). We also sampled 44 unselected Caucasian neonates whose allele distribution and modal repeat length (19 repeats) was indistinguishable from adult controls (data not shown).…”

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confidence: 99%

“…We have used two Caucasian populations which have previously been used in published studies. 13,18 These cohorts were analyzed independently in Europe and in the USA, to determine if the presence of longer CAG repeats in hSKCa3 is associated with neuropsychiatric disorders. Caucasian patients with schizophrenia were compared with ethnically matched, unrelated, screened adult controls.…”

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confidence: 99%

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Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder?

et al. 1998

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Many human hereditary neurodegenerative diseases are caused by expanded CAG repeats, and anonymous CAG expansions have also been described in schizophrenia and bipolar disorder. We have isolated and sequenced a novel human cDNA encoding a neuronal, small conductance calcium-activated potassium channel (hSKCa3) that contains two arrays of CAG trinucleotide repeats. The second CAG repeat in hSKCa3 is highly polymorphic in control individuals, with alleles ranging in size from 12 to 28 repeats. The overall allele frequency distribution is significantly different in patients with schizophrenia compared to ethnically matched controls (Wilcoxon Rank Sum test, P = 0.024), with CAG repeats longer than the modal value being over-represented in patients (Fisher Exact test, P = 0.0035). A similar, non-significant, trend is seen for patients with bipolar disorder. These results provide evidence for a possible association between longer alleles in the hSKCa3 gene and both of these neuropsychiatric diseases, and emphasize the need for more extensive studies of this new gene. Small conductance calcium-activated K + channels play a critical role in determining the firing pattern of neurons. These polyglutamine repeats may modulate hSKCa3 channel function and neuronal excitability, and thereby increase disease risk when combined with other genetic and environmental effects.

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The unstable trinucleotide repeat story of major psychosis

et al. 2000

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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...

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Analysis of the CAG repeats in the SCA1 and B37 genes in schizophrenic and bipolar I disorder patients: Tentative association between B37 and schizophrenia

Cited by 13 publications

References 45 publications

Genetic association study of a polymorphic CAG repeats array of calcium-activated potassium channel (KCNN3) gene and schizophrenia among the Chinese population from Taiwan

Genetic association study of a polymorphic CAG repeats array of calcium-activated potassium channel (KCNN3) gene and schizophrenia among the Chinese population from Taiwan

Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder?

The unstable trinucleotide repeat story of major psychosis

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