Abstract
Recently, a Leu309Met mutation in WKL1 (MLC1, KIAA0027), a gene mapped to chromosome 22q13.33, was reported to co-segregate with periodic catatonia, a clinical sub-type of schizophrenia, in seven members of an extended pedigree.1 WKL1 encodes a putative membrane protein expressed exclusively in the brain, particularly in the amygdala, nucleus caudatus, thalamus, and hippocampus.1 We screened WKL1 for etiologic mutations in 28 probands from the United States who were given a consensus diagnosis of schizophrenia and met at least one of these criteria: (1) were from multiplex schizophrenia families where at least two schizophrenic subjects were reported to display catatonic behavior at sometime during the course of their illness; or (2) were from multiplex schizophrenia families where, in a genome scan for schizophrenia susceptibility loci, evidence for excess allele sharing among affected family members for markers in the 22q13 region was seen. In addition, 15 affected subjects from 15 German pedigrees were similarly screened for causative mutations. This German cohort exhibited the catatonia phenotype but had ambiguous linkage to 22q13 and included the mutation-positive proband as a positive control. The 43 probands were screened for base changes in WKL1: 15 SNPs in the non-coding regions of the gene, three SNPs in the 3′UTR, four synonymous coding SNPs and two non-synonymous (amino acid changing) SNPs were identified. We were able to rapidly confirm the Leu309Met nucleotide change in the positive control. No missense mutations were detected in any of the other 42 probands studied. These data exclude the role of WKL1 in schizophrenia susceptibility in the subjects studied.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Meyer J Huberth A Ortega G Syagailo YV Jatzke S Mössner R et alA missense mutation in a novel gene encoding a putative cation channel is associated with catatonic schizophrenia in a large pedigree Mol Psychiatry 2001 6 302 306
Eaton WW Epidemiology of schizophrenia Epidemiol Rev 1985 7 105 126
Brzustowicz LM Hodgkinson KA Chow EW Honer WG Bassett AS Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22 Science 2000 288 678 682
Hovatta I Varilo T Suvisaari J Terwilliger JD Ollikainen V Arajarvi R et alA genomewide screen for schizophrenia genes in an isolated Finnish subpopulation, suggesting multiple susceptibility loci Am J Hum Genet 1999 65 1114 1124
Gurling HM Kalsi G Brynjolfson J Sigmundsson T Sherrington R Mankoo BS et alGenome-wide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21–22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3–24 and 20q12.1–11.23 Am J Hum Genet 2001 68 661 673
Blouin JL Dombroski BA Nath SK Lasseter VK Wolyniec PS Nestadt G et alSchizophrenia susceptibility loci on chromosomes 13q32 and 8p21 Nat Genet 1998 20 70 73
Straub RE MacLean CJ O'Neill FA Walsh D Kendler KS Support for a possible schizophrenia vulnerability locus in region 5q22–31 in Irish families Mol Psychiatry 1997 2 148 155
Straub RE MacLean CJ O'Neill FA Burke J Murphy B Duke F et alA potential vulnerability locus for schizophrenia on chromosome 6p24–22: evidence for genetic heterogeneity Nat Genet 1995 11 287 293
Schwab SG Hallmayer J Albus M Lerer B Eckstein GN Borrmann M et alA genome-wide autosomal screen for schizophrenia susceptibility loci in 71 families with affected siblings: support for loci on chromosome 10p and 6 Mol Psychiatry 2000 5 638 649
Straub RE MacLean CJ Martin RB Ma Y Myakishev MV Harris-Kerr C et alA schizophrenia locus may be located in region 10p15-p11 Am J Med Genet 1998 81 296 301
Stober G Saar K Ruschendorf F Meyer J Nurnberg G Jatzke S et alSplitting schizophrenia: periodic catatonia-susceptibility locus on chromosome 15q15 Am J Hum Genet 2000 67 1201 1207
Pulver AE Mulle J Nestadt G Swartz KL Blouin JL Dombroski B et alGenetic heterogeneity in schizophrenia: stratification of genome scan data using co-segregating related phenotypes Mol Psychiatry 2000 5 650 653
Chiu Y-F McGrath J Thornquist M Wolyniec P Nestadt G Swartz K et alGenetic heterogeneity in schizophrenia II: conditional analyses of affected schizophrenia sibling pairs provides evidence for an interaction between markers on chromosome 8p and 14q Mol Psychiatry(in press)
Leonhard K Classifications of Endogenous Psychoses and Their Differentiated Etiology Springer: Vienna and New York 1999
Leegwater PA Yuan BQ van der Steen J Mulders J Konst AA Boor PK et alMutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts Am J Hum Genet 2001 68 831 838
Tiso N Stephan DA Nava A Bagattin A Devaney JM Stanchi F et alIdentification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2) Hum Mol Genet 2001 10 189 194
Laitinen PJ Brown KM Piippo K Swan H Devaney JM Brahmbhatt B et alMutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia Circulation 2001 103 485 490
Jones AC Austin J Hansen N Hoogendoorn B Oefner PJ Cheadle PJ et alOptimal temperature selection for mutation detection by denaturing HPLC and comparison to single-stranded conformation polymorphism and heteroduplex analysis Clin Chem 1999 45 1133 1140
Escary JL Cecillon M Maciazek J Lathrop M Tournier-Lasserve E Joutel A Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content Hum Mutat 2000 16 518 526
Kruglyak L Daly MJ Reeve-Daly MP Lander ES Parametric and nonparametric linkage analysis: a unified multipoint approach Am J Hum Genet 1996 58 1347 1363
Pulver AE Karayiorgou M Wolyniec PS Lasseter VK Kasch L Nestadt G et alSequential strategy to identify a susceptibility gene for schizophrenia: report of potential linkage on chromosome 22q12-q13.1: Part 1 Am J Med Genet 1994 54 36 43
Acknowledgements
The authors would like to express their gratitude to the families for their participation and support and to the individuals in the Epidemiology-Genetics Program in Psychiatry at Johns Hopkins Medicine who have labored for years developing the clinical data sets. Special thanks to Virginia K Lasseter for her assistance in the preparation of this manuscript. The research was supported in part by grants from the National Institutes of Mental Health (5R01MH057314) to AEP and JMD is supported by T32-MH1983307, and grants of the German Research Foundation (DFG, SFB 581) and German Ministry of research (BMBF, 01GA9802/5) to KPL.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Devaney, J., Donarum, E., Brown, K. et al. No missense mutation of WKL1 in a subgroup of probands with schizophrenia. Mol Psychiatry 7, 419–423 (2002). https://doi.org/10.1038/sj.mp.4001022
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4001022
Keywords
This article is cited by
-
Subtyping schizophrenia: implications for genetic research
Molecular Psychiatry (2006)
-
Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder
Molecular Psychiatry (2006)
-
Transmission disequilibrium test provides evidence of association between promoter polymorphisms in 22q11 gene DGCR14 and schizophrenia
Journal of Neural Transmission (2006)
-
Systematic mutation analysis of KIAA0767 and KIAA1646 in chromosome 22q-linked periodic catatonia
BMC Psychiatry (2005)
-
Multicenter linkage study of schizophrenia loci on chromosome 22q
Molecular Psychiatry (2004)