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First identification of PODXL nonsense mutations in autosomal dominant focal segmental glomerulosclerosis.
- Source :
-
Clinical science (London, England : 1979) [Clin Sci (Lond)] 2019 Jan 03; Vol. 133 (1), pp. 9-21. Date of Electronic Publication: 2019 Jan 03 (Print Publication: 2019). - Publication Year :
- 2019
-
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 the present study, we report the identification of a heterozygous nonsense PODXL mutation (c.C976T; p. 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 with 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 293T cells transfected with the pEGFP-PODXL-Arg326X or pEGFP-PODXL-Ser378X plasmid expressed significantly lower mRNA and PODXL protein compared with 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 down-regulation 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.<br /> (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Subjects :
- Adult
Aged
Animals
Asian People genetics
Case-Control Studies
China
Cytoskeletal Proteins genetics
Cytoskeletal Proteins metabolism
Female
Genetic Association Studies
Genetic Predisposition to Disease
Glomerulosclerosis, Focal Segmental diagnosis
Glomerulosclerosis, Focal Segmental ethnology
Glomerulosclerosis, Focal Segmental metabolism
HEK293 Cells
Heredity
Heterozygote
Humans
Male
Mice
Middle Aged
Pedigree
Phenotype
Podocytes pathology
Proteinuria ethnology
Proteinuria genetics
Proteinuria metabolism
RNA Stability
Renal Insufficiency ethnology
Renal Insufficiency genetics
Renal Insufficiency metabolism
Risk Factors
Sialoglycoproteins metabolism
Young Adult
rho GTP-Binding Proteins genetics
rho GTP-Binding Proteins metabolism
rhoA GTP-Binding Protein
Codon, Nonsense
Glomerulosclerosis, Focal Segmental genetics
Podocytes metabolism
Sialoglycoproteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1470-8736
- Volume :
- 133
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Clinical science (London, England : 1979)
- Publication Type :
- Academic Journal
- Accession number :
- 30523047
- Full Text :
- https://doi.org/10.1042/CS20180676