Actin -related protein 3 (Arp3) is mutated in proteinuric BUF/Mna rats.
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 (L)111(F) 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.
Central Pharmaceutical Research Institute, Japan Tobacco Inc, Yokohama, 236-0004, Japan.
Kiyotaka
K
Akiyama
Hiroyuki
H
Morita
Shiro
S
Suetsugu
Seiko
S
Kuraba
Yasuharu
Y
Numata
Yoshihisa
Y
Yamamoto
Kiyoko
K
Inui
Terukuni
T
Ideura
Noriko
N
Wakisaka
Kiyoko
K
Nakano
Hiroaki
H
Oniki
Tadaomi
T
Takenawa
Mutsushi
M
Matsuyama
Ashio
A
Yoshimura
D051378:Actin-Related Protein 3 / Q000737:chemistry / Q000235:genetics*; D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D033481:Chromosomes, Mammalian; D005786:Gene Expression Regulation; D005819:Genetic Markers; D006649:Histocompatibility Antigens / Q000235:genetics; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008126:Lod Score; D008969:Molecular Sequence Data; D008970:Molecular Weight; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics; D020161:Physical Chromosome Mapping; D017434:Protein Structure, Tertiary; D011507:Proteinuria / Q000235:genetics*; D040641:Quantitative Trait Loci; D051381:Rats; D011915:Rats, Inbred BUF; D017422:Sequence Analysis, DNA
D051378:Actin-Related Protein 3; D000199:Actins; D005819:Genetic Markers; D006649:Histocompatibility Antigens; D050505:Mutant Proteins