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

作者：Ilya M. Chumakov, Marta L. BLUMENFELD, Oxana Guerassimenko, Laurent Cavarec, Marta Palicio, Hadi Abderrahim, Lydie Bougueleret, Caroline Barry, Hiroaki Tanaka, Philippe La Rosa, Anne Puech, N. Tahri, Annick Cohen-Akenine, Sylvain Delabrosse, Sebastien Lissarrague, Françoise-Pascaline Picard, Karelle Maurice, Laurent Essioux, Philippe Millasseau, Pascale Grel, Virginie Debailleul, A M Simon, Dominique Caterina, Isabelle Dufaure, Kattayoun Malekzadeh, Maria Belova, Jian-Jian Luan, Michel Bouillot, Jean-Luc Sambucy, Gwenaël Primas, Martial Saumier, Nadia Boubkiri, Sandrine Martin-Saumier, M Nasroune, Hélène Peixoto, Arnaud Delaye, Virginie Pinchot, M Bastucci, Sophie Guillou, Magali Chevillon, Ricardo Sáinz‐Fuertes, S Meguenni, Joan Aurich‐Costa, Dorra Chérif, Anne Gimalac, Cornelia M. van Duijn, D. Gauvreau, Gail Ouelette, Isabel Fortier, John Realson, Tatiana Sherbatich, N Riazanskaia, Evgeny Ivanovich Rogaev, Peter Raeymaekers, Jeroen Aerssens, Frank Konings, Walter H.M.L. Luyten, Fabio M. Macciardi, Pak Chung Sham, Richard E. Straub, Daniel R. Weinberger, Nadine Cohen, Daniel Blair Cohen · 发表于：Proceedings of the National Academy of Sciences · 年份：2002 · DOI：10.1073/pnas.182412499 · 被引用次数：831 · 研究领域：Amino Acid Enzymes and Metabolism、Tryptophan and brain disorders、Neuroscience and Neuropharmacology Research

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...