Actin -related protein 3 (Arp3) is mutated in proteinuric BUF/Mna rats |
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| Authors: | Kiyotaka Akiyama Hiroyuki Morita Shiro Suetsugu Seiko Kuraba Yasuharu Numata Yoshihisa Yamamoto Kiyoko Inui Terukuni Ideura Noriko Wakisaka Kiyoko Nakano Hiroaki Oniki Tadaomi Takenawa Mutsushi Matsuyama Ashio Yoshimura |
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| Affiliation: | (1) Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc, Yokohama 236-0004, Japan;(2) Division of Nephrology, Department of Medicine, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama 227-8501, Japan;(3) Department of Biochemistry, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan;(4) PRESTO Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan;(5) Department of Epigenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan;(6) Electron Microscopy Laboratory, Showa University Fujigaoka Hospital, Yokohama 227-8501, Japan;(7) Department of Surgical Pathology, School of Medicine, Fujita Health University Toyoake, Aichi 470-1192, Japan |
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| Abstract: | The BUF/Mna strain of rat is a model of focal and segmental glomerulosclerosis (FSGS) in which a quantitative trait locus (QTL) for proteinuria, Pur1, has been identified. The aim of the present study was to identify candidates for the Pur1 gene. To narrow the Pur1 QTL, we performed fine QTL mapping and single nucleotide polymorphism (SNP) genotyping. To identify candidate genes, sequencing and gene-expression analyses of all genes contained in the narrowed locus were conducted. The narrowed Pur1 region contained 25 genes. Among these genes, only the Arp3 gene was mutated in the BUF/Mna strain; it contained a missense mutation that caused an L111F substitution. This leucine is conserved across species. Gene-expression analysis failed to identify any other candidate genes for Pur1. Arp3-mediated actin assembly abnormalities were visible in immunohistochemical and electron microscopic examinations of podocytes in old BUF/Mna rats. Taken together, these data suggest that Arp3 is a candidate for the Pur1 gene. This observation is consistent with our growing recognition that abnormal signaling-induced assembly of actin in podocytes leads to the development of FSGS. Nucleotide sequence data reported in this article are available in the DDBJ/EMBL/GenBank database under accession numbers AB292042-292043 and AB294577-294580. |
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