| 1 | PLoS ONE 2011 -1 6: e26049 |
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| 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 |
| 2 | J. Biol. Chem. 2014 Oct 289: 27585-603 |
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| PMID | 25157101 |
| Title | Dystroglycan binding to ?-neurexin competes with neurexophilin-1 and neuroligin in the brain. |
| Abstract | ?-Neurexins (?-Nrxn) are mostly presynaptic cell surface molecules essential for neurotransmission that are linked to neuro-developmental disorders as autism or schizophrenia. Several interaction partners of ?-Nrxn are identified that depend on alternative splicing, including neuroligins (Nlgn) and dystroglycan (?DAG). The trans-synaptic complex with Nlgn1 was extensively characterized and shown to partially mediate ?-Nrxn function. However, the interactions of ?-Nrxn with ?DAG, neurexophilins (NXPH1) and Nlgn2, ligands that occur specifically at inhibitory synapses, are incompletely understood. Using site-directed mutagenesis, we demonstrate the exact binding epitopes of ?DAG and NXPH1 on Nrxn1? and show that their binding is mutually exclusive. Identification of an unusual cysteine bridge pattern and complex type glycans in NXPH1 ensure binding to the second laminin/neurexin/sex hormone binding (LNS2) domain of Nrxn1?, but this association does not interfere with Nlgn binding at LNS6. ?DAG, in contrast, interacts with both LNS2 and LNS6 domains without inserts in splice sites SS#2 or SS#4 mostly via LARGE (like-acetylglucosaminyltransferase)-dependent glycans attached to the mucin region. Unexpectedly, binding of ?DAG at LNS2 prevents interaction of Nlgn at LNS6 with or without splice insert in SS#4, presumably by sterically hindering each other in the u-form conformation of ?-Nrxn. Thus, expression of ?DAG and NXPH1 together with alternative splicing in Nrxn1? may prevent or facilitate formation of distinct trans-synaptic Nrxn·Nlgn complexes, revealing an unanticipated way to contribute to the identity of synaptic subpopulations. |
| SCZ Keywords | schizophrenia |
| 3 | Genetika 2015 Jul 51: 799-811 |
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| PMID | 26410934 |
| Title | [The Role of Neurotrophins and Neurexins Genes in the Risk of Paranoid Schizophrenia in Russians and Tatars]. |
| Abstract | schizophrenia affects about 1% of the population. Its etiology is not fully understood. Environmental conditions certainly contribute to the development of schizophrenia, but the determining factor is genetic predisposition: the coefficient of heritability of schizophrenia is about 80%, which is typical for the most highly heritable multifactorial diseases. Polymorphic loci of genes of enzymes and receptors involved in the processes of neuroprotection and neurotrophia play significant role in the development of this disease. In this paper we investigated 48 polymorphic variants of genes of the neurotrophins and neurexins family (BDNF, NTRK2, NTRK3, NGF, NXPH1, and NRXN1) in Russian and Tatar cases and in a control group living in the Republic of Bashkortostan. The results of this study confirm the important role of neurotrophin and neurexin genes in paranoid schizophrenia development. |
| SCZ Keywords | schizophrenia |