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

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

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    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.

    Original languageEnglish
    Pages (from-to)13675-13680
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume99
    Issue number21
    DOIs
    Publication statusPublished - 15 Oct 2002

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    ASJC Scopus subject areas

    • General

    Cite this

    Chumakov, I., Blumenfeld, M., Guerassimenko, O., Cavarec, L., Palicio, M., Abderrahim, H., Bougueleret, L., Barry, C., Tanaka, H., La Rosa, P., Puech, A., Tahri, N., Cohen-Akenine, A., Delabrosse, S., Lissarrague, S., Picard, F. P., Maurice, K., Essioux, L., Millasseau, P., ... Cohen, D. (2002). Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 99(21), 13675-13680. https://doi.org/10.1073/pnas.182412499