First identification of PODXL nonsense mutations in autosomal dominant focal segmental glomerulosclerosis

• DOI: 10.1042/cs20180676
• Publication Date: 2018-12-06T19:20:44Z
• Authors: Fu-Jun Lin; Lei Yao; Xue-Qing Hu; Fan Bian; Gang Ji; Geng-Ru Jiang; Daniel P. Gale; Hong-Qi Ren
• Keywords: Podocalyxin; Nonsense mutation

Recently, a novel heterozygous missense mutation c.T1421G (p. L474R) in the PODXL gene encoding podocalyxin was identified an autosomal dominant focal segmental glomerulosclerosis (AD-FSGS) pedigree. However, this appeared not to impair function, and it is necessary identify new mutations determine their causative role for FSGS. In present study, we report identification of nonsense (c.C976T; p. Arg326X) Chinese pedigree featured by proteinuria renal insufficiency with AD inheritance whole exome sequencing (WES). Total mRNA protein abundance were decreased available peripheral blood cell samples two affected patients undergoing hemodialysis, compared those healthy controls hemodialysis without mutation. We another (c.C1133G; p.Ser378X) British-Indian AD-FSGS WES. vitro study showed that, human embryonic kidney 293T cells transfected pEGFP-PODXL-Arg326X or pEGFP-PODXL-Ser378X plasmid expressed significantly lower wild-type plasmid. Blocking nonsense-mediated decay (NMD) restored amount mutant proteins, which indicated that pathogenic effect likely due NMD, resulting deficiency. Functional consequences caused inferred siRNA knockdown cultured podocytes down-regulation resulted RhoA ezrin activities, migration stress fiber formation. Our results provided data implicating development