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Sequencing of Five Left–Right Cerebral Asymmetry Genes in a Cohort Of Original article 75 Sequencing of five left–right cerebral asymmetry genes in a cohort of schizophrenia and schizotypal disorder patients from Russia Anastasia Levchenkoa, Stepan Davtianb, Natalia Petrovab and Yegor Malashicheva Objective Schizophrenia is a severe psychiatric disorder, Conclusion This is the first study in which multiple affecting B1% of the human population. The genetic candidate genes for cerebral LR asymmetry and contribution to schizophrenia is significant, but the schizophrenia have been analyzed by sequencing. genetics are complex and many aspects of brain The approach to study the genetics of schizophrenia from functioning, from neural development to synapse structure, the perspective of an LR cerebral asymmetry disturbance seem to be involved in the pathogenesis. A novel way to deserves more attention. Psychiatr Genet 24:75–80 c study the molecular causes of schizophrenia is to study the 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. genetics of left–right (LR) brain asymmetry, the disease Psychiatric Genetics 2014, 24:75–80 feature often observed in schizophrenic patients. Keywords: candidate gene, cerebral asymmetry, DNA mutational analysis, Methods In this study, we analyzed by sequencing five novel genetic variant, schizophrenia candidate LR cerebral asymmetry genes in a cohort of 95 aDepartment of Embryology, Faculty of Biology and bDepartment of Psychiatry schizophrenia and schizotypal disorder patients from Saint and Narcology, Faculty of Medicine, Saint Petersburg State University, Petersburg, Russia. The gene list included LMO4, LRRTM1, Saint Petersburg, Russia FOXP2, the PCDH11X/Y gene pair, and SRY. Correspondence to Yegor Malashichev, PhD, Department of Embryology, Saint Petersburg State University, Universitetskaya nab. 7/9, Saint Results We found 17 previously unreported variants in the Petersburg 199034, Russia Tel: + 7 812 3289453; fax: + 7 812 3289569; 0 genes LRRTM1, FOXP2, LMO4, and PCDH11X in the 3 -UTR e-mails: [email protected], [email protected] and 50-UTR. The variants might contribute toward an Received 5 September 2013 Revised 23 September 2013 altered mRNA processing, which could lead to altered Accepted 8 October 2013 mRNA amounts in developing neurons of the brain and establishment of an incorrect LR asymmetry profile. Introduction (Burmeister et al., 2008; Tiwari et al., 2010; Gejman et al., Schizophrenia is a severe mental disorder, affecting B1% 2011; Girard et al., 2011; Rodriguez-Murillo et al., 2012). of any human population (Freedman, 2003). It is Recently, apart from long-established linkage and associa- characterized by ‘positive’ symptoms, including halluci- tion studies of genetics of schizophrenia, new approaches nations, delusions, and disorganized speech and ‘negative’ have emerged, studying de-novo copy number variations symptoms, including social withdrawal and affective and point mutations by resequencing [reviewed in Rees flattening. As a result, patients affected by schizophrenia et al. (2012) and Rodriguez-Murillo et al. (2012)]. These often show dysfunction in work, interpersonal relation- various studies discovered genes important mostly in ships, or self-care. The disorder has a complex clinical neural development, neurotransmission, and immune picture that can additionally vary within the same system (Tiwari et al., 2010). Indeed, a widely accepted individual during his/her life course, leading to the notion view of schizophrenia is that of a neurodevelopmental of ‘schizophrenias’, rather than a single homogeneous disorder, affecting normal brain development during disorder (Boshes et al., 2012). Given the complex clinical embryogenesis and childhood (Rapoport et al., 2005; picture, it is not surprising that the genetics of Fatemi and Folsom, 2009). An aberrant brain develop- schizophrenia are non-Mendelian. Schizophrenia has an ment apparently leads to the multiple structural and important genetic component, up to 80% of factors functional brain abnormalities observed in schizophrenic leading to pathogenesis being genetic (Sullivan et al., patients (Ross et al., 2006; Schmitt et al., 2011). One of 2003), and the genetic studies of schizophrenia are the hallmarks of a schizophrenic brain is reduced or even advancing, leading to the discovery of B20 candidate reversed left–right (LR) asymmetry of the brain struc- genes, whose role was supported by multiple studies tures (Sommer et al., 2001; Oertel-Knochel and Linden, 2011). This finding allowed to propose that genes important for the establishment of LR asymmetry Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this of the human brain are implicated in schizophrenia article on the journal’s website (www.psychgenetics.com). (Crow et al., 1989). The main difficulty in this direction 0955-8829 c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/YPG.0000000000000021 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 76 Psychiatric Genetics 2014, Vol 24 No 2 of investigation of schizophrenia genetics is that the behavior, self-neglect, disorientation, conceptual disorga- genes responsible for the establishment of LR asymmetry of nization, blunted affect, emotional withdrawal, motor the human brain are hardly known, and they might not retardation, tension, uncooperativeness, excitement, dis- be the same as the well-described genes that determine tractibility, motor hyperactivity, and mannerism-posturing LR asymmetry of the viscera (Malashichev and (Ventura et al., 1993; Dingemans et al., 1995). Each item Wassersug, 2004; Malashichev, 2006; Sun and Walsh, is rated with a score: 1 – not present, 2 – very mild, 2006; Corballis, 2009; Crow et al., 2009). In particular, 3 – mild, 4 – moderate, 5 – moderately severe, 6 – individuals with situs inversus totalis of the viscera do not severe, and 7 – extremely severe; in Table 1 and in always show in parallel a functional or a structural re- Supplementary Table, Supplemental digital content 1, versal of brain LR asymmetry [reviewed in Malashichev http://links.lww.com/PG/A93, we present the total scores (2006) and Renteria (2012)]. Nevertheless, several (the sum of scores) for the patients. candidates for the role of the genes determining cerebral asymmetry have been described in the literature. The goal of this study was to screen by sequencing five genes, Genetic screening described in the literature, with a possible role in the After literature review, five candidate genes for LR development of LR asymmetry of the human brain, in a asymmetry of the human brain were identified. This list cohort of individuals with a diagnosis of schizophrenia. is similar to the one proposed previously (Crow et al., Therefore, the working hypothesis was that these genes 2009), but incorporated an additional sex chromosome were mutated; the mutations led to altered LR asym- gene, SRY. The list includes LRRTM1 (Leucine Rich Repeat metry of the brain and, eventually, to schizophrenia Transmembrane Neuronal 1), associated with schizophrenia in these patients. and handedness (Francks et al., 2007); FOXP2 (Forkhead Box P2), found to be mutated in a speech disorder and Methods associated with functional asymmetry of the brain (Lai Ethics statement et al., 2001; Ocklenburg et al., 2013b); LMO4 (Lim Domain Written informed consent was obtained from all the Only 4), found to be consistently asymmetrically ex- participants. The participants have not had a compro- pressed in the perisylvian human cortex and apparently mised capacity/ability to consent because they are determining cerebral asymmetry (Sun et al., 2005; Li et al., outpatients at an ambulatory care clinic and are not 2013); PCDH11X/Y (protocadherin 11 X-linked and psychotic. The experiments comply with the current laws protocadherin 11 Y-linked), a gene pair, expressed in the of the country (The Russian Federation) in which they developing human brain and interacting with molecular were conducted, and were also approved by the pathways, implicated in schizophrenia and body asym- responsible authorities at the institute (Faculty of metry, with a proposed role in determining brain Medicine, Saint Petersburg State University, Saint asymmetry, schizophrenia, and different sex-specific Petersburg, The Russian Federation) where the work clinical pictures (Priddle and Crow, 2013); and SRY has been carried out. In addition, the research was carried (sex-determining region Y), apparently determining a differ- out in full compliance with the Code of Ethics of the ent pattern of activity in dopaminergic neurons in the World Medical Association (Declaration of Helsinki). male brain and a different brain morphology in general in men, in comparison with women (Czech et al., 2012). For Patients more details, see a literature review of the five candidate The participants are outpatients at the Saint Petersburg genes in Supplemental digital content 2 (http://links.lww. State University psychiatric ambulatory care clinic; all of com/PG/A94). them reside in Saint Petersburg, Russia. The cohort of 95 Genomic DNA was extracted from peripheral blood patients was selected on the basis of the diagnostic leukocytes using the FlexiGene DNA Kit (Qiagen, criteria of The International Statistical Classification of Hilden, Germany) following procedures recommended Diseases and Related Health Problems, 10th Revision by the manufacturer. For each gene,
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