Is the <i>WKL1</i> gene associated with schizophrenia?

Kaganovich, M.; Peretz, Asher; Ritsner, Michael S.; Abu-Shach, U. Bening; Attali, B.; Navon, Ruth

doi:10.1002/ajmg.b.20115

Cited by 20 publications

(11 citation statements)

References 21 publications

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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. 38 According to the regional LD pattern discussed above it does not seem likely that the Indian MLC1 signal and the present BRD1 association represent the same susceptibility locus, unless the population of Southern India has a different and more extended LD pattern.…”

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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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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“…The sixth polymorphism, c.925C4A, has been debated in several works [Devaney et al, 2002;Kaganovich et al, 2004;Leegwater et al, 2002a,b;McQuillin et al, 2002;Meyer et al, 2001;Rubie et al, 2003;Teijido et al, 2004], which describe the possible association of a leucine to methionine change at position 309 with schizophrenia. A recent work reported on the association of schizophrenia and bipolar disorder with MLC1 mutations [Verma et al, 2005].…”

Section: Polymorphismsmentioning

confidence: 99%

Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis ofMLC1

et al. 2006

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Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive cerebral white matter disorder in children. This disease is histopathologically characterized by myelin splitting and intramyelinic vacuole formation. MLC is caused by mutations in the gene MLC1, which encodes a novel protein, MLC1. Since the first report, 50 mutations in this gene have been found. Mutations occur throughout the entire coding region and include all different types: 11 splice-site mutations; one nonsense mutation; 24 missense mutations; and 14 deletions and insertions. Until now, six polymorphisms within the coding sequence of MLC1 had been reported. In about 20% of the patients with a typical clinical and MRI picture, no mutations in the MLC1 gene are found. Several of the families, in which no mutations are found, also do not show linkage with the MLC1 locus, which suggests a second gene involved in MLC. The absence of mutations may also be the consequence of performing standard mutation analysis that can miss heterozygous deletions, mutations in the promoter, 3' and 5' untranslated regions (UTRs), and intron mutations, which may influence the amino acid composition of the end product. In this work we describe 13 novel mutations, including those found with extended mutation analysis on MLC patients. This study shows that extended mutation analysis is a valuable tool to identify at least some of the missing mutations. Therefore, we suggest extended mutation analysis for the MLC1 gene, if no mutations are found during standard analysis.

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“…Based on the myelin vacuolation present in MLC patients and the low homology of MLC1 to ion channels, it has been suggested that MLC1 could have a role in ion transport processes linked to water movements. Unfortunately, functional evidence is lacking, because no ion channel activity has been detected after expression of MLC1 in heterologous systems (Kaganovich et al, 2004; Teijido et al, 2004). …”

Section: Introductionmentioning

confidence: 99%

Knockdown of MLC1 in primary astrocytes causes cell vacuolation: A MLC disease cell model

Duarri

Heredia

Capdevila-Nortes

et al. 2011

Neurobiology of Disease

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Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy, in the majority of cases caused by mutations in the MLC1 gene. MRI from MLC patients shows diffuse cerebral white matter signal abnormality and swelling, with evidence of increased water content. Histopathology in a MLC patient shows vacuolation of myelin, which causes the cerebral white matter swelling. MLC1 protein is expressed in astrocytic processes that are part of blood- and cerebrospinal fluid-brain barriers. We aimed to create an astrocyte cell model of MLC disease. The characterization of rat astrocyte cultures revealed MLC1 localization in cell-cell contacts, which contain other proteins described typically in tight and adherent junctions. MLC1 localization in these contacts was demonstrated to depend on the actin cytoskeleton; it was not altered when disrupting the microtubule or the GFAP networks. In human tissues, MLC1 and the protein Zonula Occludens 1 (ZO-1), which is linked to the actin cytoskeleton, co-localized by EM immunostaining and were specifically co-immunoprecipitated. To create an MLC cell model, knockdown of MLC1 in primary astrocytes was performed. Reduction of MLC1 expression resulted in the appearance of intracellular vacuoles. This vacuolation was reversed by the co-expression of human MLC1. Reexamination of a human brain biopsy from an MLC patient revealed that vacuoles were also consistently present in astrocytic processes. Thus, vacuolation of astrocytes is also a hallmark of MLC disease.

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Is the WKL1 gene associated with schizophrenia?

Cited by 20 publications

References 21 publications

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

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

Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis ofMLC1

Knockdown of MLC1 in primary astrocytes causes cell vacuolation: A MLC disease cell model

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