A missense mutation in a novel gene encoding a putative cation channel is associated with catatonic schizophrenia in a large pedigree

Meyer, Jobst; Huberth, A; Ortega, Guillermo J.; Syagailo, Yana V.; Jatzke, Susanne; Mößner, Rainald; Strom, Tim M.; Ulzheimer-Teuber, Isabel; Stöber, Gerald; Schmitt, Angelika; Lesch, Klaus‐Peter

doi:10.1038/sj.mp.4000869

Cited by 101 publications

(69 citation statements)

References 19 publications

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“…We sequenced exon 11 and its intron/exon boundaries in 174 UK schizophrenics, including cases of 22 cases of catatonic schizophrenia, and did not identify any individual that contained the mutation described by Meyer et al 1 However, we did observe a novel insertion/deletion polymorphism (with a predicted amino acid insertion of AGEVSGLWGGG 350 -351), one-missense substitution (N344S) and two synonymous substitutions in exon 11 (1174C4T and 1192T4C). In addition, we also identified a nucleotide substitution in intron 11 (IVS11+27A4G (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…1 The protein is predicted to have eight transmembrane domains and one of these occurs in exon 11. 1,2 Structural prediction analyses of the mutation found in the large pedigree with catatonic schizophrenia indicates that the presence of this missense mutation is likely to result in conformational changes of the mutant protein.…”

Section: Discussionmentioning

confidence: 99%

“…1 This mutation was thought to be the cause of catatonic schizophrenia in this pedigree. WKL1 is thought to encode a brain expressed non-selective cation channel.…”

Section: Introductionmentioning

confidence: 99%

“…The missense mutation, described by Meyer et al, 1 was thought to disrupt a transmembrane domain of WKL1 and would therefore be likely to affect the function of the protein, possibly increasing susceptibility to schizophrenia. The WKL1 gene has also been investigated under an alternative gene name: MLC1.…”

Section: Introductionmentioning

confidence: 99%

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A novel polymorphism in exon 11 of the WKL1 gene, shows no association with schizophrenia

et al. 2002

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A missense mutation in exon 11 of the WKL1 gene on chromosome 22 was found to be associated with cases of catatonic schizophrenia in a single large pedigree. We have screened exon 11 of the WKL1 gene in 174 cases of schizophrenia, including cases of 22 cases of catatonic schizophrenia, but could not detect the previously reported mis-sense mutation. However in exon 11, we observed an insertion/deletion polymorphism, one-missense substitution and two synonymous substitutions. In addition, we also identified a nucleotide substitution in intron 11. All these polymorphisms appeared to be in complete linkage disequilibrium with one another. The polymorphisms were also identified in a UK pedigree with schizophrenia, however the polymorphisms did not segregate with the disease. To test for potential association between these polymorphisms and schizophrenia we sequenced an equal number of UK control individuals who were free of all psychiatric symptoms and had negative family histories for mental illness; the frequency of the insertion/deletion polymorphism was not significantly different in schizophrenia cases (42 out of 348 chromosomes, allele frequency 12%) compared to normal controls (40 out of 356 chromosomes, allele frequency 11%). The insertion/deletion was found to be in Hardy Weinberg equilibrium in both the schizophrenic and control groups. The insertion/deletion is composed of repeated sequence from exon 11 and intron 11 and is predicted to affect WKL1 protein structure.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…1 This mutation was thought to be the cause of catatonic schizophrenia in this pedigree. WKL1 is thought to encode a brain expressed non-selective cation channel.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A novel polymorphism in exon 11 of the WKL1 gene, shows no association with schizophrenia

et al. 2002

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“…34 However, both the same group and others have more recently rejected this hypothesis based on more extensive analyses of a number of catatonic families. [35][36][37] Interestingly, a recent study of a Southern Indian population reported evidence of association between MLC1 and both SZ and BPD.…”

Section: Discussionmentioning

confidence: 99%

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

et al. 2006

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Linkage studies suggest that chromosome 22q12-13 may contain one or more shared susceptibility genes for schizophrenia (SZ) and bipolar affective disorder (BPD). In a Faeroese sample, we previously reported association between microsatellite markers located at 22q13.31-qtel and both disorders. The present study reports an association analysis across five genes (including 14 single nucleotide and two microsatellite polymorphisms) in this interval using a case-control sample of 162 BPD, 103 SZ patients and 200 controls. The bromodomain-containing 1 gene (BRD1), which encodes a putative regulator of transcription showed association with both disorders with minimal P-values of 0.0046 and 0.00001 for single marker and overall haplotype analysis, respectively. A specific BRD1 2-marker 'risk' haplotype showed a frequency of B10% in the combined case group versus B1% in controls (P-value 2.8 Â 10 À7 ). Expression analysis of BRD1 mRNA revealed widespread expression in mammalian brain tissue, which was substantiated by immunohistochemical detection of BRD1 protein in the nucleus, perikaryal cytosol and proximal dendrites of the neurons in the adult rat, rabbit and human CNS. Quantitative mRNA analysis in developing fetal pig brain revealed spatiotemporal differences with high expression at early embryonic stages, with intense nuclear and cytosolar immunohistochemical staining of the neuroepithelial layer and early neuroblasts, whilst more mature neurons at later embryonic stages had less nuclear staining. The results implicate BRD1 with SZ and BPD susceptibility and provide evidence that suggests a role for BRD1 in neurodevelopment.

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Spontaneous Movement Disorders in Psychiatric Patients

Richard¹,

O’Brien²,

Kurlan³

2005

Drug Induced Movement Disorders

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A missense mutation in a novel gene encoding a putative cation channel is associated with catatonic schizophrenia in a large pedigree

Cited by 101 publications

References 19 publications

A novel polymorphism in exon 11 of the WKL1 gene, shows no association with schizophrenia

A novel polymorphism in exon 11 of the WKL1 gene, shows no association with schizophrenia

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

Spontaneous Movement Disorders in Psychiatric Patients

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