Schizophrenia Patient Shows a Rare Interleukin 15 Receptor alpha Variant Disrupting Signal Transduction.

BACKGROUND: Schizophrenia is a complex and debilitating mental disorder with strong heritability. Its pathogenesis involves immune dysregulation. Interleukin 15 and interleukin 15 receptor alpha(IL-15Rα) are classical immune molecules. They also help maintain normal brain function, leading to our hypothesis that IL-15Rα gene(IL- 15RA) variants contribute to the pathogenesis of schizophrenia. OBJECTIVE: We determine whether the genetic variants of IL-15RA are associated with the development and progression of schizophrenia and whether IL-15RA single nucleotide polymorphism(SNP) plays a key role in downstream signaling transduction. METHODS AND RESULTS: We sequenced IL-15RA exon from 132 Chinese schizophrenic patients and identified a rare variant(rs528238821) in a patient diagnosed with catatonic schizophrenia and ankylosing spondylitis(AS). We overexpressed this missense variant in cells driven by pBI-CMV vector. The cells showed attenuated STAT3 phosphorylation in response to interleukin15. CONCLUSION: IL-15RA mutation is rare in schizophrenic patients but interfered with IL- 15Rα intracellular signal transduction. Given the similarity of symptoms of catatonic schizophrenia and the known phenotype of IL-15Rα knockout mice, gene variation might offer diagnostic value for sub-types of schizophrenia.

Microarray Analysis of Human Blood During Electroconvulsive Therapy.

INTRODUCTION: Electroconvulsive therapy (ECT) is currently regarded as a significant treatment option for intractable psychiatric disorders, such as catatonic schizophrenia or treatment-resistant depression; however, the underlying molecular mechanism for its therapeutic effect remains obscure. METHODS: Employing microarray analysis (Human Genome U133 Plus 2.0 Array; Affymetrix, United States) of cDNA derived from the peripheral blood of patients with catatonic schizophrenia (n = 5), we detected a significant change in 145 genes (0.68%) before and after modified ECT (mECT). Moreover, we performed quantitative polymerase chain reaction validation of genes that had previously been suggested to be functionally related to schizophrenia. RESULTS: Of 4 genes examined (AKT3, TCF7, PPP3R1, and GADD45B), only TCF7 was increased during the mECT procedure (P = 0.0025). DISCUSSION: This study describes the first attempt to uncover the molecular mechanism of mECT using a microarray assay of mRNA derived from peripheral blood, and our results suggest that the TCF family may play a role in the functional mechanism of mECT.

Genetics of schizophrenia in the context of integrative psychiatry.

Epidemiological studies suggest a strong heritability in schizophrenia. Positive family history is the greatest risk factor for developing schizophrenia. However, regarding the genetic factors in schizophrenia, there is a lot of the inconsistency (i.e. non-replication) in the literature of the associations of different genes with schizophrenia. The presence of a single gene is neither sufficient, nor necessary to cause schizophrenia. The understanding of the genetic basis of schizophrenia is complex. Besides different gene polymorphisms, numerous environmental factors, interacting with genes, contribute to susceptibility to schizophrenia. Such factors include the use of street drugs, childhood head injury, maternal infection during pregnancy, paternal age at conception, stressful life events and urban upbringing. While knowing genetic risks, integrative psychiatry may have a role in reducing other modifiable risk factors, including reduction of stress level, stress management strategies, family consultation/education, education against street drugs use, treatment of prodromal symptoms and development of social skills.

Successful use of olanzapine in adolescent monozygotic twins with catatonic schizophrenia resistant to electroconvulsive therapy: case report.

We describe a case of monozygotic (MZ) male twins (14.6 years old) who suffered from a severe form of catatonic schizophrenia. On admission, the principal symptoms of the brothers were stupor, mutism, catatonic posturing, rigidity, negativism, and refusal of food and liquids. They were treated with electroconvulsive therapy (ECT) with no effect (twin A) and almost no effect (twin B). Both twins improved with initiation of olanzapine therapy. Twin B showed a marked improvement by week 2 on a dose of 10 mg daily (qd). Improvement in twin A was seen by week 4 on a dose of 15 mg qd. Twin B was discharged after 8 weeks and twin A after 11 weeks of olanzapine treatment. This appears to be the first report on concordant positive responses to olanzapine in MZ twins with catatonic schizophrenia, as well as, the first report on concordant resistance to ECT.

MLC1 polymorphisms are specifically associated with periodic catatonia, a subgroup of chronic schizophrenia.

BACKGROUND: The MLC1, located on chromosome 22q13.33, has been suggested as a risk gene for schizophrenia, especially the periodic catatonia subtype. An initially identified missense mutation was found to be extremely rare in other patient cohorts; however, a recent report again argued for an association of two intronic MLC1 single nucleotide polymorphisms (SNPs) with schizophrenia and bipolar disorder. METHODS: A case-control study of these polymorphisms as well as SNPs in the transcriptional control region of MLC1 was conducted in 212 chronic schizophrenic patients, 56 of which suffered from periodic catatonia, 106 bipolar patients, and 284 controls. RESULTS: Both intronic and promoter polymorphisms were specifically and significantly associated with periodic catatonia but not schizophrenia or bipolar disorder in general. A haplotype constructed from all polymorphisms was also associated with periodic catatonia. CONCLUSIONS: The MLC1 variation is associated with periodic catatonia; whether it constitutes a susceptibility or a modifier gene has to be determined.

Shared susceptibility region on chromosome 15 between autism and catatonia.

We have compiled significant linkage results from 20 genome scans for the autism syndrome disorder (ASD) and 2 for catatonia in schizophrenia (SZ). Localization of the markers has been updated across the studies using the same cytological (Genetic Location Database), physical (National Center for Biological Information), and genetic (Marshfield) maps. Eight autosomal chromosomes (1, 2, 3, 7, 9, 13, 15, and 17) showed significant linkages with ASD, and one with catatonia (15). Chromosome 15 was further characterized for SZ genome scans (N = 4) since catatonia was observed in SZ patients, for candidate genes for ASD and catatonia, and for the numerous chromosomal rearrangement and abnormalities associated to ASD. From these results, we observed that four potential susceptibility regions for ASD could be observed on chromosome 15 at 15q11-q13, 15q14-q21, 15q22-q23, and 15q26, respectively. All the four regions were shared between ASD and SZ, with 15q15-q21 being also shared with catatonia. Strong candidate genes, such as gamma-aminobutyric acid receptor B3, A5, and G3, have shown associations with ASD at 15q11-q13 susceptibility region where the majority of the chromosomal rearrangements are also found. On the other hand, negative association results were observed at 15q14-q21 susceptibility region for catatonia with the genes encoding the zinc transporter SLC30A4, the cholinergic receptor nicotinic alpha polypeptide 7, and the delta-like 4 Drosophila. Further, fine mapping and candidate gene analyses are needed to highlight potential common genes between ASD and catatonia for this chromosome.

Systematic mutation analysis of KIAA0767 and KIAA1646 in chromosome 22q-linked periodic catatonia.

BACKGROUND: Periodic catatonia is a familial subtype of schizophrenia characterized by hyperkinetic and akinetic episodes, followed by a catatonic residual syndrome. The phenotype has been evaluated in two independent genome-wide linkage scans with evidence for a major locus on chromosome 15q15, and a second independent locus on chromosome 22qtel. METHODS: In the positional and brain-expressed candidate genes KIAA0767 and KIAA1646, we searched for variants in the complete exons and adjacent splice-junctions as well as in parts of the 5'- and 3'-untranslated regions by means of a systematic mutation screening in individuals from chromosome 22q-linked pedigrees. RESULTS: The mutation scan revealed 24 single nucleotide polymorphisms, among them two rare codon variants (KIAA0767: S159I; KIAA1646: V338G). However, both were neither found segregating with the disease in the respective pedigree nor found at a significant frequency in a case-control association sample. CONCLUSION: Starting from linkage signals at chromosome22qtel in periodic catatonia, we screened two positional brain-expressed candidate genes for genetic variation. Our study excludes genetic variations in the coding and putative promoter regions of KIAA0767 and KIAA1646 as causative factors for periodic catatonia.

MLC1 gene is associated with schizophrenia and bipolar disorder in Southern India.

BACKGROUND: Chromosome 22q13 has shown linkage with schizophrenia (SCZ) and bipolar affective disorder (BPAD). A missense mutation in MLC1 (putative cation-channel gene on 22q13) co-segregating with periodic catatonic schizophrenia has been reported. We have investigated the relationship of MLC1 with SCZ and BPAD in Southern India. METHODS: All exons and flanking intronic sequences of MLC1 were screened for novel variations. Case-control (216 BPAD, 193 SCZ, 116 control subjects) and family-based analyses (113 BPAD, 107 SCZ families) were performed to evaluate association of MLC1 with these disorders. RESULTS: We found 33 MLC1 sequence variations, including three novel mutations: Val210Ile, Leu308Gln, and Arg328His in six BPAD cases and Val210Ile in one control individual. Minor allele of a common variation, ss16339182 (in approximately 6 Kb Linkage-Disequilibrium [LD]-block) was associated with BPAD in case-control (p = .03) and family-based analyses (transmitted/nontransmitted [T/NT]-44/20; p = .003). Association was observed for rs2235349 and rs2076137 with SCZ and ss16339163 with BPAD in case-control study. Using Block 2 haplotype tagging single nucleotide polymorphisms (htSNPs), GC haplotype revealed association (p = .02) and excess transmission (p = .002) with BPAD. CONCLUSIONS: Association of MLC1 with SCZ and BPAD suggests involvement of a common pathway. Rare missense mutations and common variants associated with BPAD favors hypothesis about likely involvement of both rare and common polymorphisms in etiology of this complex disorder.

Is the WKL1 gene associated with schizophrenia?

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.

Mutation analysis of the zinc transporter gene SLC30A4 reveals no association with periodic catatonia on chromosome 15q15.

The zinc transporter gene SLC30A4, located on chromosome 15q15-q21, has previously been reported to show altered expression patterns in post mortem analysis of the brains of schizophrenic patients. As a positional candidate we investigated SLC30A4 in the chromosome 15q15-linked schizophrenic phenotype periodic catatonia (MIM 605419), by means of a systematic mutation screening in affected individuals from exceptionally large pedigrees with perfect co-segregation of a chromosomal segment between marker D15S1042 and D15S659 in all affected individuals. The mutation scan revealed no genetic variants within the coding and the putative promoter region of SLC30A4 and, thus, excludes a genetic association of SLC30A4 with catatonic schizophrenia.

Mutational analysis of the connexin 36 gene (CX36) and exclusion of the coding sequence as a candidate region for catatonic schizophrenia in a large pedigree.

The murine connexin 36 gene (Cx36) encodes a gap-junction channel protein which is preferentially expressed in brain and retina. The human orthologue CX36 is located on chromosome 15q14, a region recently shown to contain a susceptibility gene for hereditary catatonic schizophrenia. Therefore, CX36 was considered as a positional candidate for mutational analysis. Three polymorphic sites within CX36 were found by sequencing the two exons, the intron-exon boundaries and the putative promoter region of the gene derived from patients and control subjects. No variant exclusively cosegregates with the disease in a large pedigree that mainly supports the chromosome 15q14 locus, providing evidence that CX36 is not causative for the pathogenesis of catatonic schizophrenia in this family.

No missense mutation of WKL1 in a subgroup of probands with schizophrenia.

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.

Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an inherited neurologic disorder with macrocephaly before the age of one and slowly progressive deterioration of motor functions. Magnetic resonance imaging shows diffusely abnormal and swollen white matter of the cerebral hemispheres and the presence of subcortical cysts in the anterior-temporal region and often also in the frontoparietal region. Mutations in the MLC1 gene, encoding a putative membrane protein, have been recently identified as a cause for MLC. Here, we describe 14 new mutations in 18 patients. Two identified polymorphisms lead to alterations of amino acid residues. The role, suggested by others, of a mutation in the MLC1gene in catatonic schizophrenia and the possible function of the MLC1 protein as a cation channel are discussed.

Exclusion of the neuronal nicotinic acetylcholine receptor alpha7 subunit gene as a candidate for catatonic schizophrenia in a large family supporting the chromosome 15q13-22 locus.

The gene encoding the neuronal nicotinic acetylcholine receptor alpha7 subunit (CHRNA7) is located on chromosome 15q13.2. This region was suggested to be involved in the etiopathogenesis of: (a) schizophrenia combined with a neurophysiological deficit; (b) lithium-responsive bipolar disorder; and (c) familial catatonic schizophrenia (periodic catatonia). Therefore, members of a large family with periodic catatonia strongly supporting the chromosome 15q13-22 region were genotyped with polymorphic markers localized around the CHRNA7 locus. A recombination event distally of marker D15S144 leading to the exclusion of the CHRNA7 locus from this candidate region was detected in one branch of the pedigree. This result provides strong evidence that a gene located telomeric to CHRNA7 is causative for the pathogenesis of catatonic schizophrenia in this family.

A missense mutation in a novel gene encoding a putative cation channel is associated with catatonic schizophrenia in a large pedigree.

Schizophrenia is a common and etiologically heterogeneous disorder. Although inheritance of schizophrenic syndromes is complex with genetic and environmental factors contributing to the clinical phenotype, periodic catatonia, a familial subtype of catatonic schizophrenia, appears to be transmitted in an autosomal dominant manner. We report here that a Leu309Met mutation in WKL1, a positional candidate gene on chromosome 22q13.33 encoding a putative non-selective cation channel expressed exclusively in brain, co-segregates with periodic catatonia in an extended pedigree. Structural analyses revealed that this missense mutation results in conformational changes of the mutant protein. Our results not only underscore the importance of genetic mechanisms in the etiology of schizophrenic syndromes, but also provide a better understanding of the pathogenesis and incapacitating course of catatonic schizophrenia and related disorders.

Mutational analysis of the neuronal cadherin gene CELSR1 and exclusion as a candidate for catatonic schizophrenia in a large family.

The cadherin gene CELSR1 is specifically expressed in the brain and located on chromosome 22q13.33, a region that has recently been shown to be involved in the etiopathogenesis of familial catatonic schizophrenia. The gene is a strong positional candidate and was considered for mutational analysis. A total of 17 allelic variants of CELSR1 was found by sequencing all 35 exons, intron-exon junctions, and the putative promoter region by screening two patients from a large family mainly supporting this locus, and three control subjects in a first step. No variant exclusively co-segregates with the disease in the large pedigree, providing evidence that CELSR1 is not causative for the pathogenesis of catatonic schizophrenia in this family.

Catatonic schizophrenia in Croatia.

A representative sample of schizophrenic subjects was collected for epidemiological and clinical follow-up in 1972 from the pool of 8069 patients registered in the Croatian Psychotics Case Register (CPCR). This sample comprised 402 patients (207 males and 195 females), who were followed up until 1990/91. The diagnosis of schizophrenia, catatonic type according to ICD-8 (V/295.2), was made in 59 cases (14.7%; 28 males, 31 females) at least once in the course of the follow-up. This study presents data concerning the diagnostic instability of the catatonic subtype during the long-term follow-up. As subtype diagnoses were frequently changed over the course of illness, at the end of the follow-up, the diagnosis of catatonic schizophrenia was only confirmed in 11 (18.6%) cases. Positive family history of psychosis was found in 44.1% of catatonic patients, a percent significantly greater than the corresponding figure for all non-catatonic schizophrenic subtypes combined (20.1%). This study provides preliminary evidence that the catatonic subtype of schizophrenia is a separate diagnostic entity with a high familial loading.