Copy number variation of the SELENBP1 gene in schizophrenia
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RESEARCH
Open Access
Copy number variation of the SELENBP1 gene in schizophrenia Shirly Amar1, Ofer Ovadia2, Wolfgang Maier3, Richard Ebstein4, RH Belmaker1, Dan Mishmar2*, Galila Agam1*
Abstract Background: Schizophrenia is associated with rare copy-number (CN) mutations. Screening for such alleles genome-wide, though comprehensive, cannot study in-depth the causality of particular loci, therefore cannot provide the functional interpretation for the disease etiology. We hypothesized that CN mutations in the SELENBP1 locus could associate with the disorder and that these mutations could alter the gene product’s activity in patients. Methods: We analyzed SELENBP1 CN variation (CNV) in blood DNA from 49 schizophrenia patients and 49 controls (cohort A). Since CN of genes may vary among tissues, we investigated SELENBP1 CN in age- sex- and postmortem interval-matched cerebellar DNA samples from 14 patients and 14 controls (cohort B). Since CNV may either be denovo or inherited we analyzed CNV of the SELENBP1 locus in blood DNA from 26 trios of schizophrenia probands and their healthy parents (cohort C). SELENBP1 mRNA levels were measured by real-time PCR. Results: In cohort A reduced CN of the SELENBP1 locus was found in four patients but in none of the controls. In cohort B we found reduced CN of the SELENBP1 locus in two patients but in none of the controls. In cohort C three patients exhibited drastic CN reduction, not present in their parents, indicating de-novo mutation. A reduction in SELENBP1 mRNA levels in the postmortem cerebellar samples of schizophrenia patients was found. Conclusions: We report a focused study of CN mutations in the selenium binding-protein1 (SELENBP1) locus previously linked with schizophrenia. We provide evidence for recurrence of decreased CN of the SELENBP1 locus in three unrelated patients’ cohorts but not in controls, raising the possibility of functional involvement of these mutations in the etiology of the disease.
Background Genomic deletion, duplication and insertion, designated copy number variation (CNV), are found in all human beings, could be either common, rare or de novo [1] and may influence gene expression and phenotypic variation [2-6]. CNV have been linked to the pathogenesis of both monogenic and complex disorders [7-13] including brain-related disorders such as schizophrenia [14-17]. Specifically, twenty five percent of subjects carrying a 3-Mb microdeletion in chromosome 22q11.2 exhibited psychiatric manifestations including autism, attention-deficit hyperactivity disorder (ADHD) and schizophrenia [18]. Recent whole genome CNV screens revealed significant association of rare CNVs in several * Correspondence: [email protected]; [email protected] 1 Psychiatry Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, and Mental Health Center, Beersheva, Israel 2 Department of Life Sciences and National Institute of Biotechnology (NIBN), Ben-Gurion University of the Negev, Beer Sheva, Israel
loci with schizophrenia [16,19-21]. Confirmed de novo
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