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

Lin, F-J; Yao, L; Hu, X-Q; Bian, F; Ji, G; Jiang, G-R; Gale, DP; (2019) First identification of PODXL nonsense mutations in autosomal dominant focal segmental glomerulosclerosis. Clinical Science , 133 (1) pp. 9-21. 10.1042/CS20180676. Green open access

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Abstract

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

Type: Article
Title: First identification of PODXL nonsense mutations in autosomal dominant focal segmental glomerulosclerosis
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1042/CS20180676
Publisher version: https://doi.org/10.1042/CS20180676
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: focal segmental glomerulosclerosis, genetic kidney disease, podocyte, proteinuria, renal failure
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10064737
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