Association of WKL1/MLC1 with Catatonic Schizophrenia

Association of WKL1/MLC1 1 Lesch KP et al. Mol Psychiatry 2001; 6: 302–306. with catatonic schizophrenia 2 Leegwater PAJ et al. Am J Hum Genet 2001; 68: 831–838. Molecular Psychiatry (2002) 7, 1037. doi:10.1038/ Reply concerning KIAA0027 sj.mp.4001142 (WKL1, MLC1) and psychosis:

SIR – Recently, Lesch et al associated a missense white matters mutation, L309M, in WKL1 on chromosome 22 qtel with catatonic schizophrenia (CS) in an extended family.1 Molecular Psychiatry (2002) 7, 1037–1038. The mutation did not occur in a large control group doi:10.1038/ sj.mp.4001200 and it was concluded that the mutation was involved in the etiology of the disorder. Furthermore, it was sug- SIR – We appreciate the comments from Leegwater and gested that the gene codes for a new type of cation colleagues regarding our recently published article transporter based on a low similarity to voltage-depen- about the possibility that the L309M variant of the KIAA0027 (WKL1, MLC1) gene may cause catatonic dent potassium channels. The mode of inheritance was 1 dominant and parallels were made with movement dis- schizophrenia (SCZD10, MIM 605419). We are aware orders caused by dominant mutations in ion trans- of their report on the involvement of KIAA0027 in the pathogenesis of megalencephalic leukoencephalopathy porter genes. For instance, benign familial neonatal 2 epilepsy can be caused by frameshift mutations in with subcortical cysts (MLC, MIM 604004) and we agree with Leegwater and coworkers that the hypoth- KCNQ2. The impact of this finding is illustrated by the esis of an involvement of KIAA0027 in schizophrenia fact that three abstracts of the 2001 meeting of the requires confirmation in other affected families or American Society of Human Genetics were dedicated patients. A patient with catatonic schizophrenia who to the search for additional WKL1 mutations in schizo- is likely to be homo- or hemizygous for six adjacent phrenics, yet none were found. In the light of our rare genetic markers from the chromosome 22q13.33 results with the WKL1 gene we suggest that the con- region is currently being investigated for the presence clusions of Lesch et al should be reconsidered. In the of a deletion in the 3Ј region of KIAA0027.3 However, same gene, which we named MLC1, we found 26 differ- we cannot rule out that a mutation in a gene different ent recessive mutations that cause Megalencephalic from KIAA0027 in the 4 cM telomeric region of chro- Leukoencephalopathy with Subcortical Cysts (MLC, mosome 22 causes catatonic schizophrenia. The neu- MIM 604004).2 The patients from 24 families are homo- ronal cadherin gene CELSR1 which is exclusively zygous or compound heterozygous for MLC1 expressed in brain has meanwhile been excluded from mutations. Eleven mutations introduce stopcodons or the candidate gene panel by mutational analysis. Inves- frameshifts. These data show convincingly that MLC1 tigation of other candidate genes from this chromo- is involved in MLC. We have never observed catatonic somal region should help to confirm or exclude a poss- schizophrenia or any other form of schizophrenia in ible role of KIAA0027 in the pathogenesis of MLC patients or family members who are carriers. In chromosome 22-related catatonic schizophrenia. view of the range of mutations found in MLC families Homozygous and compound heterozygous mutations we conclude that the amino acid substitution described of KIAA0027 cause recessively inherited MLC, thus by Lesch et al does not dominantly cause CS. Further- supporting the notion that the KIAA0027 protein plays more, analyzing the amino acid sequence of the MLC1 a critical role in myelination and in diseases of the product, we were not able to identify any of the amino white matter. This potential function of KIAA0027 is acid sequence motifs for cation channels as defined in interesting in the light of the increasingly appreciated the URL www.expasy.ch/prosite. The individuals with hypothesis that some forms of schizophrenia-like psy- the L309M allele may be carriers for MLC. Of course, chosis represent leukoencephalopathies or myelino- another gene on chromosome 22qtel could be involved pathies. Several lines of evidence indicate that a var- in CS. iety of neurodegenerative disorders with a genetic, vascular, or inflammatory etiology that lead to white matter dysfunction and disrupted cortical-striatal-lim- PAJ Leegwater, PKI Boor, JC Pronk and MS van der bic connectivity are more or less commonly associated Knaap with psychotic episodes. For instance, symptoms of Department of Child Neurology, Free University Medi- acute psychosis including complex auditory halluci- cal Center, The Netherlands nations and bizarre delusions are frequently observed in a neurological disorder distantly related to MLC, Correspondence should be addressed to MS van der Knaap. E-mail: metachromatic leukodystrophy (MLD, MIM 250100) MS.vanderknaapȰvumc.nl (for review see Hyde et al4). MLD is caused by