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Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia.

ABSTRACT: A map of 191 single-nucleotide polymorphism (SNPs) was built across a 5-Mb segment from chromosome 13q34 that has been genetically linked to schizophrenia. DNA from 213 schizophrenic patients and 241 normal individuals from Canada were genotyped with this marker set. Two 1,400- and 65-kb regions contained markers associated with the disease. Two markers from the 65-kb region were also found to be associated to schizophrenia in a Russian sample. Two overlapping genes G72 and G30 transcribed in brain were experimentally annotated in this 65-kb region. Transfection experiments point to the existence of a 153-aa protein coded by the G72 gene. This protein is rapidly evolving in primates, is localized to endoplasmic reticulum/Golgi in transfected cells, is able to form multimers and specifically binds to carbohydrates. Yeast two-hybrid experiments with the G72 protein identified the enzyme d-amino acid oxidase (DAAO) as an interacting partner. DAAO is expressed in human brain where it oxidizes d-serine, a potent activator of N-methyl-D-aspartate type glutamate receptor. The interaction between G72 and DAAO was confirmed in vitro and resulted in activation of DAAO. Four SNP markers from DAAO were found to be associated with schizophrenia in the Canadian samples. Logistic regression revealed genetic interaction between associated SNPs in vicinity of two genes. The association of both DAAO and a new gene G72 from 13q34 with schizophrenia together with activation of DAAO activity by a G72 protein product points to the involvement of this N-methyl-d-aspartate receptor regulation pathway in schizophrenia.

SUBMITTER: Chumakov I

PROVIDER: S-EPMC129739 | biostudies-literature | 2002 Oct

REPOSITORIES: biostudies-literature

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Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia.

Chumakov Ilya I Blumenfeld Marta M Guerassimenko Oxana O Cavarec Laurent L Palicio Marta M Abderrahim Hadi H Bougueleret Lydie L Barry Caroline C Tanaka Hiroaki H La Rosa Philippe P Puech Anne A Tahri Nadia N Cohen-Akenine Annick A Delabrosse Sylvain S Lissarrague Sébastien S Picard Françoise-Pascaline FP Maurice Karelle K Essioux Laurent L Millasseau Philippe P Grel Pascale P Debailleul Virginie V Simon Anne-Marie AM Caterina Dominique D Dufaure Isabelle I Malekzadeh Kattayoun K Belova Maria M Luan Jian-Jian JJ Bouillot Michel M Sambucy Jean-Luc JL Primas Gwenael G Saumier Martial M Boubkiri Nadia N Martin-Saumier Sandrine S Nasroune Myriam M Peixoto Hélène H Delaye Arnaud A Pinchot Virginie V Bastucci Mariam M Guillou Sophie S Chevillon Magali M Sainz-Fuertes Ricardo R Meguenni Said S Aurich-Costa Joan J Cherif Dorra D Gimalac Anne A Van Duijn Cornelia C Gauvreau Denis D Ouellette Gail G Fortier Isabel I Raelson John J Sherbatich Tatiana T Riazanskaia Nadejda N Rogaev Evgeny E Raeymaekers Peter P Aerssens Jeroen J Konings Frank F Luyten Walter W Macciardi Fabio F Sham Pak C PC Straub Richard E RE Weinberger Daniel R DR Cohen Nadine N Cohen Daniel D

Proceedings of the National Academy of Sciences of the United States of America 20021003 21

A map of 191 single-nucleotide polymorphism (SNPs) was built across a 5-Mb segment from chromosome 13q34 that has been genetically linked to schizophrenia. DNA from 213 schizophrenic patients and 241 normal individuals from Canada were genotyped with this marker set. Two 1,400- and 65-kb regions contained markers associated with the disease. Two markers from the 65-kb region were also found to be associated to schizophrenia in a Russian sample. Two overlapping genes G72 and G30 transcribed in br ...[more]

PMID: 12364586

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Project description:BackgroundSchizophrenia is a neurodegenerative disorder that occurs worldwide and can be difficult to diagnose. It is the foremost neurological disorder leading to suicide among patients in both developed and underdeveloped countries. D-amino acid oxidase activator (DAOA), also known as G72, is directly implicated in the glutamateric hypothesis of schizophrenia. It activates D-amino acid oxidase, which oxidizes D-serine, leading to modulation of the N-methyl-D-aspartate receptor.MethodsMODELLER (9v10) was utilized to generate three dimensional structures of the DAOA candidate gene. The HOPE server was used for mutational analysis. The Molecular Evolutionary Genetics Analysis (MEGA5) tool was utilized to reconstruct the evolutionary history of the candidate gene DAOA. AutoDock was used for protein-ligand docking and Gramm-X and PatchDock for protein-protein docking.ResultsA suitable template (1ZCA) was selected by employing BLASTp on the basis of 33% query coverage, 27% identity and E-value 4.9. The Rampage evaluation tool showed 91.1% favored region, 4.9% allowed region and 4.1% outlier region in DAOA. ERRAT demonstrated that the predicted model had a 50.909% quality factor. Mutational analysis of DAOA revealed significant effects on hydrogen bonding and correct folding of the DAOA protein, which in turn affect protein conformation. Ciona was inferred as the outgroup. Tetrapods were in their appropriate clusters with bifurcations. Human amino acid sequences are conserved, with chimpanzee and gorilla showing more than 80% homology and bootstrap value based on 1000 replications. Molecular docking analysis was employed to elucidate the binding mode of the reported ligand complex for DAOA. The docking experiment demonstrated that DAOA is involved in major amino acid interactions: the residues that interact most strongly with the ligand C28H28N3O5PS2 are polar but uncharged (Gln36, Asn38, Thr 122) and non-polar hydrophobic (Ile119, Ser171, Ser21, Ala31). Protein-protein docking simulation demonstrated two ionic bonds and one hydrogen bond involving DAOA. Lys-7 of the receptor protein interacted with Lys-163 and Asp-2037. Tyr-03 interacted with Arg-286 of the ligand protein and formed a hydrogen bond.ConclusionThe predicted interactions might serve to inhibit the disease-related allele. It is assumed that current bioinformatics methods will contribute significantly to identifying, analyzing and curing schizophrenia. There is an urgent need to develop effective drugs for schizophrenia, and tools for examining candidate genes more accurately and efficiently are required.

Dataset Information

Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia.

Publications

Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia.

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