| 1 | Mol. Psychiatry 2002 -1 7: 412-5 |
|---|---|
| PMID | 11986985 |
| Title | An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. |
| Abstract | Morphological alterations in the brains of schizophrenia patients suggest that neurodevelopmental dysfunction is involved in the etiology of the disease.(1) Such dysfunction may be due to functional alterations of cell adhesion molecules, which play important roles in cell migration, axonal growth, fasciculation, synaptogenesis, and synaptic remodeling. We screened for mutations in the coding region of the close homologue to L1 gene (CHL1), which is located on human chromosome 3p26, in 24 Japanese patients with schizophrenia. A missense polymorphism (Leu17Phe) in the signal peptide region was identified. A case-control comparison revealed significantly higher frequencies of the Leu/Leu genotype (P = 0.004) and the Leu allele (P = 0.006) in 282 Japanese schizophrenic patients than in 229 Japanese control subjects. The estimated odds ratio for schizophrenia was 1.83 (95% CI, 1.28-2.26) for the Leu/Leu genotype compared with the other genotypes. An association between this CHL1 gene polymorphism and schizophrenia supports the notion that cell adhesion molecules are involved in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Mol. Psychiatry 2002 -1 7: 412-5 |
| PMID | 11986985 |
| Title | An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. |
| Abstract | Morphological alterations in the brains of schizophrenia patients suggest that neurodevelopmental dysfunction is involved in the etiology of the disease.(1) Such dysfunction may be due to functional alterations of cell adhesion molecules, which play important roles in cell migration, axonal growth, fasciculation, synaptogenesis, and synaptic remodeling. We screened for mutations in the coding region of the close homologue to L1 gene (CHL1), which is located on human chromosome 3p26, in 24 Japanese patients with schizophrenia. A missense polymorphism (Leu17Phe) in the signal peptide region was identified. A case-control comparison revealed significantly higher frequencies of the Leu/Leu genotype (P = 0.004) and the Leu allele (P = 0.006) in 282 Japanese schizophrenic patients than in 229 Japanese control subjects. The estimated odds ratio for schizophrenia was 1.83 (95% CI, 1.28-2.26) for the Leu/Leu genotype compared with the other genotypes. An association between this CHL1 gene polymorphism and schizophrenia supports the notion that cell adhesion molecules are involved in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | J. Neurobiol. 2003 Oct 57: 67-80 |
| PMID | 12973829 |
| Title | Aberrant neuronal connectivity in CHL1-deficient mice is associated with altered information processing-related immediate early gene expression. |
| Abstract | In humans, loss or alteration of the CHL1/CALL gene may contribute to mental impairment associated with the 3p-syndrome, caused by distal deletions of the short (p) arm of chromosome 3, and schizophrenia. Mice deficient for the Close Homologue of L1 (CHL1) show aberrant connectivity of hippocampal mossy fibers and olfactory sensory axons, suggesting participation of CHL1 in the establishment of neuronal networks. Furthermore, behavioral studies showed that CHL1-deficient mice react differently towards novel experimental environments. These data raise the hypothesis that processing of information, possibly novel versus familiar, may be altered in the absence of CHL1. To test this hypothesis, brain activities were investigated after presentation of a novel, familiar, or neutral gustatory stimulus using metabolic mapping with ((14)C)-2-deoxyglucose (2-DG) and analysis of mRNA expression of the immediate early genes (IEGs) c-fos and arg 3.1/arc by in situ hybridization. 2-DG labeling revealed only small differences between CHL1-deficient and wild-type littermate mice. In contrast, while the specific novelty-induced increase in c-fos expression was maintained in most of the brain areas analyzed, c-fos mRNA expression was similar after the novel and familiar taste in several brain areas of the CHL1-deficient mice. Furthermore, in these mutants, arg 3.1/arc expression was slightly reduced after the novel taste and increased after the familiar taste, leading to a similar arg 3.1/arc mRNA expression after both stimuli. Our results indicate that, in contrast to controls, CHL1-deficient mice might process novel and familiar information similarly and suggest that the altered neuronal connectivity in these mutants disturbs information processing at the molecular level. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Brain Res. 2004 Dec 1029: 131-4 |
| PMID | 15533325 |
| Title | Impairment of sensorimotor gating in mice deficient in the cell adhesion molecule L1 or its close homologue, CHL1. |
| Abstract | Mutations in the gene encoding the cell adhesion molecule L1 or its close homologue, CHL1 (close homologue of L1), cause brain dysfunction in both humans and mice. Here we report that prepulse inhibition (PPI) of the acoustic startle response is impaired in mice deficient in either L1 or CHL1. This newly identified feature may provide a basis for using these mice as models for sensorimotor gating impairment found in some neuropsychiatric disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Schizophr. Res. 2005 Mar 73: 269-74 |
| PMID | 15653271 |
| Title | Case-control association study of the close homologue of L1 (CHL1) gene and schizophrenia in the Chinese population. |
| Abstract | The close homolog of L1 (CHL1), located on human chromosome 3p26.1, is a newly identified member of the L1 family of cell adhesion molecules which play important roles in cell migration, axonal growth, and synaptic remodeling. A positive association has been reported between a missense polymorphism in CHL1 gene and schizophrenia in the Japanese population [Sakurai, K., Migita, O., Toru, M., Arinami, T., 2002. An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. Mol. Psychiatry 7, 412-415]. An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. In order to test this finding, we genotyped four SNPs in the gene in the Han Chinese population using a sample of 560 cases and 576 controls. Analysis of allele frequencies in both samples also showed strong association between SNP rs2272522 (the same marker studied by K. Sakurai) and the disease (X2=31.591, P<0.000001, OR=1.745, 95% CI=1.435-2.121). Our results confirm the positive association between CHL1 gene and schizophrenia and indicate that CHL1 may be involved in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Biochem. Soc. Trans. 2010 Apr 38: 445-51 |
| PMID | 20298200 |
| Title | Confirmed rare copy number variants implicate novel genes in schizophrenia. |
| Abstract | Understanding how cognitive processes including learning, memory, decision making and ideation are encoded by the genome is a key question in biology. Identification of sets of genes underlying human mental disorders is a path towards this objective. schizophrenia is a common disease with cognitive symptoms, high heritability and complex genetics. We have identified genes involved with schizophrenia by measuring differences in DNA copy number across the entire genome in 91 schizophrenia cases and 92 controls in the Scottish population. Our data reproduce rare and common variants observed in public domain data from >3000 schizophrenia cases, confirming known disease loci as well as identifying novel loci. We found copy number variants in PDE10A (phosphodiesterase 10A), CYFIP1 [cytoplasmic FMR1 (Fragile X mental retardation 1)-interacting protein 1], K(+) channel genes KCNE1 and KCNE2, the Down's syndrome critical region 1 gene RCAN1 (regulator of calcineurin 1), cell-recognition protein CHL1 (cell adhesion molecule with homology with L1CAM), the transcription factor SP4 (specificity protein 4) and histone deacetylase HDAC9, among others (see http://www.genes2cognition.org/SCZ-CNV). Integrating the function of these many genes into a coherent model of schizophrenia and cognition is a major unanswered challenge. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | J. Hum. Genet. 2010 May 55: 285-92 |
| PMID | 20339380 |
| Title | An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes. |
| Abstract | schizophrenia is a highly complex inheritable disease characterized by numerous genetic susceptibility elements, each contributing a modest increase in risk for the disease. Although numerous linkage or association studies have identified a large set of schizophrenia-associated loci, many are controversial. In addition, only a small portion of these loci overlaps with the large cumulative pool of genes that have shown changes of expression in schizophrenia. Here, we applied a genomic gene-function approach to identify susceptibility loci that show direct effect on gene expression, leading to functional abnormalities in schizophrenia. We carried out an integrated analysis by cross-examination of the literature-based susceptibility loci with the schizophrenia-associated expression gene list obtained from our previous microarray study (Journal of Human Genetics (2009) 54: 665-75) using bioinformatic tools, followed by confirmation of gene expression changes using qPCR. We found nine genes (CHGB, SLC18A2, SLC25A27, ESD, C4A/C4B, TCP1, CHL1 and CTNNA2) demonstrate gene-function correlation involving: synapse and neurotransmission; energy metabolism and defense mechanisms; and molecular chaperone and cytoskeleton. Our findings further support the roles of these genes in genetic influence and functional consequences on the development of schizophrenia. It is interesting to note that four of the nine genes are located on chromosome 6, suggesting a special chromosomal vulnerability in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Pharmacogenomics 2011 Feb 12: 171-84 |
| PMID | 21332311 |
| Title | Genome-wide expression profiling of human lymphoblastoid cell lines identifies CHL1 as a putative SSRI antidepressant response biomarker. |
| Abstract | Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressants for treating major depression. However, approximately 30% of patients do not respond sufficiently to first-line antidepressant drug treatment and require alternative therapeutics. Genome-wide studies searching for SSRI response DNA biomarkers or studies of candidate serotonin-related genes so far have given inconclusive or contradictory results. Here, we present an alternative transcriptome-based genome-wide approach for searching antidepressant drug-response biomarkers by using drug-effect phenotypes in human lymphoblastoid cell lines (LCLs). We screened 80 LCLs from healthy adult female individuals for growth inhibition by paroxetine. A total of 14 LCLs with reproducible high and low sensitivities to paroxetine (seven from each phenotypic group) were chosen for genome-wide expression profiling with commercial microarrays. The most notable genome-wide transcriptome difference between LCLs displaying high versus low paroxetine sensitivities was a 6.3-fold lower (p = 0.0000256) basal expression of CHL1, a gene coding for a neuronal cell adhesion protein implicated in correct thalamocortical circuitry, schizophrenia and autism. The microarray findings were confirmed by real-time PCR (36-fold lower CHL1 expression levels in the high paroxetine sensitivity group). Several additional genes implicated in synaptogenesis or in psychiatric disorders, including ARRB1, CCL5, DDX60, DDX60L, ENDOD1, ENPP2, FLT1, GABRA4, GAP43, MCTP2 and SPRY2, also differed by more than 1.5-fold and a p-value of less than 0.005 between the two paroxetine sensitivity groups, as confirmed by real-time PCR experiments. Genome-wide transcriptional profiling of in vitro phenotyped LCLs identified CHL1 and additional genes implicated in synaptogenesis and brain circuitry as putative SSRI response biomarkers. This method might be used as a preliminary tool for searching for potential depression treatment biomarkers. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | PLoS ONE 2011 -1 6: e26049 |
| PMID | 22016809 |
| Title | Copy number variants in extended autism spectrum disorder families reveal candidates potentially involved in autism risk. |
| Abstract | Copy number variations (CNVs) are a major cause of genetic disruption in the human genome with far more nucleotides being altered by duplications and deletions than by single nucleotide polymorphisms (SNPs). In the multifaceted etiology of autism spectrum disorders (ASDs), CNVs appear to contribute significantly to our understanding of the pathogenesis of this complex disease. A unique resource of 42 extended ASD families was genotyped for over 1 million SNPs to detect CNVs that may contribute to ASD susceptibility. Each family has at least one avuncular or cousin pair with ASD. Families were then evaluated for co-segregation of CNVs in ASD patients. We identified a total of five deletions and seven duplications in eleven families that co-segregated with ASD. Two of the CNVs overlap with regions on 7p21.3 and 15q24.1 that have been previously reported in ASD individuals and two additional CNVs on 3p26.3 and 12q24.32 occur near regions associated with schizophrenia. These findings provide further evidence for the involvement of ICA1 and NXPH1 on 7p21.3 in ASD susceptibility and highlight novel ASD candidates, including CHL1, FGFBP3 and POUF41. These studies highlight the power of using extended families for gene discovery in traits with a complex etiology. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Asia Pac Psychiatry 2013 Mar 5: 17-23 |
| PMID | 23857787 |
| Title | Significant association of close homologue of L1 gene polymorphism rs2272522 with schizophrenia in Qatar. |
| Abstract | Previous reports have found that polymorphisms in the close homologue of L1 (CHL1) gene located on chromosome 3p26 are associated with schizophrenia among different ethnic populations. The aim of this study was to examine the associations of single nucleotides polymorphisms (SNPs) of the CHL1 gene locus, including rs2055314 (C/T), rs2272522 (C/T) and rs331894 (A/G), with schizophrenia in the Qatari population. An association case control study was carried out on 86 Qatari schizophrenic patients from the Psychiatry Hospital, Hammed Medical Corporation, Qatar and 88 Qatari unrelated, healthy, control subjects. schizophrenia was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) criteria for schizophrenia by two independent psychiatrists. Genotyping of the SNPs rs2055314 (C/T), rs2272522 (C/T) and rs331894 (A/G) was conducted using the 5' nuclease assay with the TaqMan MGB probe and an ABI 7500. Individuals with the rs2272522 TT genotype had approximately 4.2 times greater risk of schizophrenia compared to individuals with the CC genotype (OR = 4.21; 95% CI: 1.12-15.53; P = 0.047). In addition, individuals carrying a T allele of the rs2272522 SNP had a significantly increased risk of schizophrenia (1.78 times) among the population (P = 0.028). SNPs rs2055314 and rs331894 had no significant association with schizophrenia. Pairwise linkage disequilibrium (LD) between the three polymorphisms was modest in the schizophrenic group. The rs2272522 polymorphism was found to exhibit a highly significant association with schizophrenia in the Qatari population. This finding supports the hypothesis that cell adhesion molecules may be involved in the etiology of this disease among Qatari patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Asia Pac Psychiatry 2013 Mar 5: 17-23 |
| PMID | 23857787 |
| Title | Significant association of close homologue of L1 gene polymorphism rs2272522 with schizophrenia in Qatar. |
| Abstract | Previous reports have found that polymorphisms in the close homologue of L1 (CHL1) gene located on chromosome 3p26 are associated with schizophrenia among different ethnic populations. The aim of this study was to examine the associations of single nucleotides polymorphisms (SNPs) of the CHL1 gene locus, including rs2055314 (C/T), rs2272522 (C/T) and rs331894 (A/G), with schizophrenia in the Qatari population. An association case control study was carried out on 86 Qatari schizophrenic patients from the Psychiatry Hospital, Hammed Medical Corporation, Qatar and 88 Qatari unrelated, healthy, control subjects. schizophrenia was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) criteria for schizophrenia by two independent psychiatrists. Genotyping of the SNPs rs2055314 (C/T), rs2272522 (C/T) and rs331894 (A/G) was conducted using the 5' nuclease assay with the TaqMan MGB probe and an ABI 7500. Individuals with the rs2272522 TT genotype had approximately 4.2 times greater risk of schizophrenia compared to individuals with the CC genotype (OR = 4.21; 95% CI: 1.12-15.53; P = 0.047). In addition, individuals carrying a T allele of the rs2272522 SNP had a significantly increased risk of schizophrenia (1.78 times) among the population (P = 0.028). SNPs rs2055314 and rs331894 had no significant association with schizophrenia. Pairwise linkage disequilibrium (LD) between the three polymorphisms was modest in the schizophrenic group. The rs2272522 polymorphism was found to exhibit a highly significant association with schizophrenia in the Qatari population. This finding supports the hypothesis that cell adhesion molecules may be involved in the etiology of this disease among Qatari patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | J. Neurochem. 2015 Nov 135: 830-44 |
| PMID | 26285062 |
| Title | Age-dependent loss of parvalbumin-expressing hippocampal interneurons in mice deficient in CHL1, a mental retardation and schizophrenia susceptibility gene. |
| Abstract | In humans, deletions/mutations in the CHL1/CALL gene are associated with mental retardation and schizophrenia. Juvenile CHL1-deficient (CHL1(-/-) ) mice have been shown to display abnormally high numbers of parvalbumin-expressing (PV(+) ) hippocampal interneurons and, as adults, display behavioral traits observed in neuropsychiatric disorders. Here, we addressed the question whether inhibitory interneurons and synaptic plasticity in the CHL1(-/-) mouse are affected during brain maturation and in adulthood. We found that hippocampal, but not neocortical, PV(+) interneurons were reduced with age in CHL1(-/-) mice, from a surplus of +27% at 1 month to a deficit of -20% in adulthood compared with wild-type littermates. This loss occurred during brain maturation, correlating with microgliosis and enhanced interleukin-6 expression. In parallel with the loss of PV(+) interneurons, the inhibitory input to adult CA1 pyramidal cells was reduced and a deficit in short- and long-term potentiation developed at CA3-CA1 excitatory synapses between 2 and 9 months of age in CHL1(-/-) mice. This deficit could be abrogated by a GABAA receptor agonist. We propose that region-specific aberrant GABAergic synaptic connectivity resulting from the mutation and a subsequently enhanced synaptic elimination during brain maturation lead to microgliosis, increase in pro-inflammatory cytokine levels, loss of interneurons, and impaired synaptic plasticity. Close homolog of L1-deficient (CHL1(-/-) ) mice have abnormally high numbers of parvalbumin (PV)-expressing hippocampal interneurons in juvenile animals, but in adult animals a loss of these cells is observed. This loss correlates with an increased density of microglia (M), enhanced interleukin-6 (IL6) production and a deficit in short- and long-term potentiation at CA3-CA1 excitatory synapses. Furthermore, adult CHL1(-/-) mice display behavioral traits similar to those observed in neuropsychiatric disorders of humans. |
| SCZ Keywords | schizophrenia, schizophrenic |