Gene and Schizophrenia K Sakurai1, O Migita1, M Toru2 and T Arinami1
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Molecular Psychiatry (2002) 7, 412–415 2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia K Sakurai1, O Migita1, M Toru2 and T Arinami1 1Department of Medical Genetics, Institute of Basic Medical Sciences, University of Tsukuba, 305–8575, Ibaraki, Japan; 2Department of Neuropsychiatry, Tokyo Medical and Dental University School of Medicine, 113–8519, Tokyo, Japan Keywords: CHL1; CALL; signal peptide; missense; associ- kDa NCAM in the hippocampi and prefrontal cortices ation; schizophrenia of patients with schizophrenia was found, though lev- 6,7 Morphological alterations in the brains of schizophrenia els of other NCAMs and L1CAM were not altered. patients suggest that neurodevelopmental dysfunction Since NCAMs function can be impaired by viral neu- is involved in the etiology of the disease.1 Such dys- roaminidase associated with maternal influenza infec- function may be due to functional alterations of cell tion during embryonic development,8 and since adhesion molecules, which play important roles in cell increased CSF NCAM and decreased CSF L1CAM lev- migration, axonal growth, fasciculation, synaptogen- els were found in affected but not non-affected twins esis, and synaptic remodeling. We screened for in a study of monozygotic discordant twins, the mutations in the coding region of the close homologue changes in NCAMs observed in schizophrenia may not to L1 gene (CHL1), which is located on human chromo- contribute to the genetic predisposition to schizo- some 3p26, in 24 Japanese patients with schizophrenia. 4 A missense polymorphism (Leu17Phe) in the signal pep- phrenia. However, schizophrenia is known to have a tide region was identified. A case-control comparison genetic component, and a cohort study suggested an revealed significantly higher frequencies of the Leu/Leu interaction between genetic risk for schizophrenia and genotype (P = 0.004) and the Leu allele (P = 0.006) in 282 obstetric complications.9,10 It is possible that mutations Japanese schizophrenic patients than in 229 Japanese in the genes encoding CAMs are part of the genetic control subjects. The estimated odds ratio for schizo- background that is influenced by environmental factors phrenia was 1.83 (95% CI, 1.28–2.26) for the Leu/Leu and lead to the abnormal neural development observed genotype compared with the other genotypes. An in schizophrenia. Genetic studies have not provided association between this CHL1 gene polymorphism and evidence for involvement of NCAM1 gene mutations schizophrenia supports the notion that cell adhesion 11 molecules are involved in the etiology of schizophrenia. in the development of schizophrenia, but a possible Molecular Psychiatry (2002) 7, 412–415. DOI: 10.1038/ association between an intronic polymorphism of the sj/mp/4000973 L1CAM gene on Xq28 and schizophrenia in male sub- jects has been reported.12 Cell adhesion molecules (CAMs) play important roles The L1 family of neural recognition molecules is part in specifying cell–cell interactions during develop- of the Ig superfamily.13 Members of the L1 family are ment, regeneration, and modification of synaptic characterized by six Ig-like domains at the N-terminus activity. In humans, mutations in the L1 cell adhesion of the protein and at least four fibronectin type III (FN) molecule (L1CAM) are associated with a neurological homologous repeats.14 Members of this family are syndrome termed CRASH, which includes corpus cal- either homophilic or heterophilic. A recently identified losum agenesis, mental retardation, adducted thumbs, close homologue of L1 (CHL1, also called CALL (cell spasticity, hydrocephalus, and a wide spectrum of adhesion L1-like)) is a member of this family and is a other clinical features. A mouse model with null powerful promoter of neurite outgrowth.14,15 CHL1 is mutation in the L1CAM gene suggests roles for L1CAM expressed during brain development at times of neurite in the mechanism of cortical dendrite differentiation outgrowth. Expression of CHL1 and L1CAM show over- as well as in guidance of callosal axons and regulation lapping but distinct patterns in neurons and glia, sug- of hippocampal development.2 gesting differential effects of L1-like molecules on An abnormality in expression of one of the CAMs neurite outgrowth.15 The continued expression of could result in the histologic abnormalities observed CHL1 throughout adulthood suggests that CHL1 pro- in the brains of individuals with schizophrenia.3 tein functions in the adult nervous system. Increased neural CAM (NCAM) and decreased L1CAM We consider CHL1 to be a candidate gene for schizo- immunoreactivities have been observed in the cerebro- phrenia on the basis of the link between abnormal neu- spinal fluid (CSF) of schizophrenic patients in com- rodevelopment and schizophrenia. The CHL1 gene is parison to immunoreactivities in normal control sub- composed of 26 exons distributed over a total length jects.4,5 A selective increase in levels of 105- to 115- of approximately 90 kb on human chromosome 3p26 Mutation search in CHL1 in schizophrenia K Sakurai et al 413 Figure 1 Genomic structure and locations of polymorphic sites in the human CHL1 gene. Numbers in parentheses indicate allele frequencies. (GenBank Accession Number AC011609). Although allele compared with the Phe17 allele (95% CI, 1.15– significant linkage of chromosome 3p26 to schizo- 1.89). This association was due to the higher frequency phrenia has not been found in genome-wide linkage of homozygosity for the Leu17 allele in the schizo- studies,16–19 it is possible that the CHL1 gene has minor phrenia group than in the control group. The estimated or modest association with the development of schizo- odds ratio for schizophrenia was 1.83 (95% CI, 1.28– phrenia. 2.26) for the Leu/Leu genotype in comparison to the We screened for mutations in the CHL1 gene by other genotypes. There was no significant association sequencing all exons and exon–intron junctions in 24 between the polymorphism and age at onset of schizo- randomly selected schizophrenia patients. The total phrenia, subtypes of schizophrenia, or the presence or length of the genomic region we examined was more absence of a family history of schizophrenia. The Leu1- than 11 kb per individual. Four variants, a C to T tran- 7Phe genotypes were not significantly associated with sition in exon 1 (320C→T, Leu17Phe), a T to A trans- onset age (P = 0.19) or subtypes (P = 0.12) in the schizo- version 3 bp upstream of exon 2 (IVS1–3T→A), a G to phrenic patients. A transition 41 bp upstream of exon 8 (IVS7–41G→A), The frequency of the G allele of the IVS7–41G/A and an A to G transition 6 bp downstream of exon 9 polymorphism was higher in the schizophrenic group (IVS9+6A→G), were identified (Figure 1). The fre- (0.60) than in the control group (0.54), though the dif- quency of each variant was 0.36, 0.01, 0.48, and 0.03, ference was not significant (P = 0.056). The Leu17Phe respectively, in 48 randomly selected control subjects and IVS7–41G/A polymorphisms were in modest link- (Figure 1). We examined associations of the Leu17Phe age disequilibrium in the schizophrenic (D = 0.06 and and IVS7–41G/A polymorphisms with schizophrenia DЈ = 0.35) and control (D = 0.07 and DЈ = 0.35) groups. by determining the genotype of these polymorphisms Therefore, the relatively high frequency of the G allele in 282 unrelated Japanese patients with schizophrenia of the IVS7–41G/A polymorphism in the schizophrenic and 229 unrelated Japanese control subjects. Genotypic group is likely to be due to an association between the distributions of these two polymorphisms did not devi- Leu17Phe polymorphism and schizophrenia in the ate significantly from Hardy–Weinberg equilibrium. population. The frequency of the Leu17 allele was significantly The leucine at amino acid 17 is contained within the higher in the schizophrenic group (0.71) than in the signal peptide (most likely cleavage site is between control group (0.63) (P = 0.006, Table 1). The estimated residues 24 and 25) and is conserved in the mouse Chl1 odds ratio for schizophrenia was 1.45 for the Leu17 protein. Signal peptides play a critical role in the tar- Table 1 Genotype and allele counts (frequencies) of the Leu17Phe and IVS7-41G/A polymorphisms of the CHL1 gene in the two study groups Polymorphism Genotype count (frequency) Allele count (frequency) Leu17Phe Leu/Leu Leu/Phe Phe/Phe P Leu Phe P Schizophrenics n = 282 145 (0.51) 110 (0.39) 27 (0.10) 0.004 400 (0.71) 164 (0.29) 0.006 Controls n = 229 84 (0.37) 119 (0.52) 26 (0.11) (2 = 11.3) 287 (0.63) 171 (0.37) IVS7-41G/A G/G G/A A/A G A Schizophrenics n = 282 100 (0.35) 138 (0.49) 44 (0.16) 0.14 338 (0.60) 226 (0.40) 0.056 Controls n = 229 64 (0.28) 119 (0.52) 46 (0.20) (2 = 3.9) 247 (0.54) 211 (0.46) The data of schizophrenic patients were compared with those of control subjects by using the 2 test (df = 2) for genotype distributions and by Fisher’s exact test (two-sided) for allele distributions. Molecular Psychiatry Mutation search in CHL1 in schizophrenia K Sakurai et al 414 geting of proteins to the endoplasmic reticulum and 76 disorganized, 12 catatonic, 37 residual, and 23 translocation of proteins across the membrane. They undifferentiated). Control subjects comprised 229 typically have three distinct domains: a positively anonymous, unrelated Japanese individuals (135 men charged amino-terminal region, a central hydrophobic and 94 women, 47.3 ± 11.5 years of age).