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

McQuillin, Andrew; Kalsi, Gursharan; Moorey, Helen; Lamb, Graham; Mayet, Soraya; Quested, Digby; Baker, Philip N.; Curtis, David; Gurling, Hugh

doi:10.1038/sj.ejhg.5200837

Cited by 14 publications

(8 citation statements)

References 5 publications

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“…1). As previously described [McQuillin et al, 2002], we observed four further polymorphisms (1093C4T, 1111T4C, 1146A4G [N344S], and IVS11-27A4G) in complete linkage disequilibrium with 1165ins33bp in all sequenced PCR templates carrying the insertion. These polymorphisms seem to form a distinct haplotype and we, thus, did not perform further systematic genotyping of these variants.…”

Section: Sequence Variation In Patients With Schizophreniasupporting

confidence: 66%

“…There was no evidence for genotypic association between the SNPs and schizophrenia. A recently described polymorphism, 1165ins33bp [McQuillin et al, 2002], was found at equal frequency in patients with schizophrenia and controls. The allele frequency of 1165ins33bp was 11.1% (n= 31) among patients with schizophrenia and 15.0% among controls (n= 31; p = 0.15), without evidence for allelic or genotypic association with schizophrenia.…”

Section: Sequence Variation In Patients With Schizophreniamentioning

confidence: 96%

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Sequence diversity ofKIAA0027/MLC1:are megalencephalic leukoencephalopathy and schizophrenia allelic disorders?

Rubie

Lichtner²,

Gärtner

et al. 2002

Hum. Mutat.

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The aim of the study is to validate the etiological role of KIAA0027/MLC1 in childhood-onset megalencephalic leukoencephalopathy with subcortical cysts (MLC) and in schizophrenia, particularly the catatonic subtype, which were reported to be allelic diseases. Among a series of five patients with MLC, four mutant alleles were detected: one case of compound heterozygosity for a splice site mutation and a six-base-pair in-frame deletion, one patient with a homozygous frameshifting insertion-deletion, and a further case heterozygous for a A157E substitution. A systematic mutation screening in 140 index cases with schizophrenia revealed 13 different single nucleotide polymorphisms (SNPs): one SNP in the 5'-UTR, seven SNPs in intronic regions, two synonymous codon variants (T52, Y199), and three coding variants. Two of them, C171F and N218K, were observed in controls at a significant frequency. The L309M variant that was previously supposed to be the causative factor for chromosome 22q(tel) linked-periodic catatonia was found nonsegregating in a further multiplex pedigree. Furthermore, a complicated 33-bp insertion/deletion polymorphism at the 5'-end of exon 11 of MLC1 was found at equal frequency among schizophrenic patients and controls. In summary, our study provides further evidence for allelic heterogeneity in megalencephalic leukoencephalopathy, excludes MLC1 as a susceptibility locus for schizophrenia, and thereby rules out that MLC and schizophrenia are allelic disorders.

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Section: Sequence Variation In Patients With Schizophreniasupporting

confidence: 66%

Section: Sequence Variation In Patients With Schizophreniamentioning

confidence: 96%

Sequence diversity ofKIAA0027/MLC1:are megalencephalic leukoencephalopathy and schizophrenia allelic disorders?

Rubie

Lichtner²,

Gärtner

et al. 2002

Hum. Mutat.

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“…The fact that the 1121A allele was not present in any of the 568 Israeli chromosomes tested suggests that his allele is either very rare or does not exist in the Israeli population. Our findings are consistent with two recently published studies that also checked the Leu309Met mutation, as well as 24 SNPs along the WKL1 gene [Devaney et al, 2002;McQuillin et al, 2002]: none of the 24 SNPs (in coding regionsynonymous and -non-synonymous SNPs, and in noncoding regions of the gene), nor the Leu309Met mutation were found to associate with SCZ These data by themselves suggest that the missence mutation Leu309Met is likely to be a neutral polymorphism and not associated with the etiology of SCZ. This is supported by the recent report that the C1121 !…”

Section: Discussionsupporting

confidence: 95%

Is the WKL1 gene associated with schizophrenia?

Kaganovich¹,

Peretz²,

Ritsner³

et al. 2003

American J of Med Genetics Pt B

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A missense mutation Leu309Met in the WKL1 (MLC1, KIAA0027) gene, mapped to 22q13.3, was reported to co-segregate with periodic catatonic schizophrenia (SCZ) in a single large German pedigree with seven affected individuals (Meyer et al. [2001: Mol Psychiatry 6:302-306]). This report raised the following questions that were dealt with in the present study: does the Leu309Met mutation have a role in SCZ, or only in catatonic SCZ? Does the mutation Leu309Met in the WKL1 gene, encoding a putative membrane protein, non-selective cation channel, have any effect on the channel activity? Is the WKL1 gene, which is expressed exclusively in brain, expressed differently in SCZ brains compared to controls? These questions were answered by screening the Leu309Met mutation in 117 Israeli Jewish patients with SCZ (55 Ashkenazi and 62 non-Ashkenazi Jews) and 176 matched controls. In search of differences in the level of WKL1 gene expression, postmortem dorsalateral prefrontal cortex of 16 schizophrenic patients and 15 controls was checked. We also measured the putative channel activity of normal WKL1 subcloned in pcDNA3 to determine the effect of the reported Leu309Met mutation. Our results argue against the involvement of WKL1 in SCZ susceptibility.

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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%

“…In a recent series of controls we found that the allelic frequency of the T allele appeared to be 0.21 (n 5 60). The second polymorphism, c.1165ins33, is a very complex rearrangement, involving an imperfect duplication of a 33-bp fragment (Table 2) [Leegwater et al, 2002b;McQuillin et al, 2002;Rubie et al, 2003]. It is present in the heterozygous form in 23% of the individuals in the European population [Rubie et al, 2003].…”

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

Cited by 14 publications

References 5 publications

Sequence diversity ofKIAA0027/MLC1:are megalencephalic leukoencephalopathy and schizophrenia allelic disorders?

Sequence diversity ofKIAA0027/MLC1:are megalencephalic leukoencephalopathy and schizophrenia allelic disorders?

Is the WKL1 gene associated with schizophrenia?

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

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