GAPVD1 and ANKFY1 mutations implicate RAB5 regulation in nephrotic syndrome

Hermle T, Schneider R, Schapiro D, Braun DA, Van Der Ven AT, Warejko JK, Daga A, Widmeier E, Nakayama M, Jobst-Schwan T, Majmundar AJ, Ashraf S, Rao J, Finn LS, Tasic V, Hernandez JD, Bagga A, Jalalah SM, El Desoky S, Kari JA, Laricchia KM, Lek M, Rehm HL, Macarthur DG, Mane S, Lifton RP, Shril S, Hildebrandt F (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Journal of the American Society of Nephrology American Society of Nephrology

Book Volume: 29

Pages Range: 2123-2138

Journal Issue: 8

DOI: 10.1681/ASN.2017121312

Abstract

Background Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of CKD. The discovery of monogenic causes of SRNS has revealed specific pathogenetic pathways, but these monogenic causes do not explain all cases of SRNS. Methods To identify novel monogenic causes of SRNS, we screened 665 patients by whole-exome sequencing. We then evaluated the in vitro functional significance of two genes and the mutations therein that we discovered through this sequencing and conducted complementary studies in podocyte-like Drosophila nephrocytes. Results We identified conserved, homozygous missense mutations of GAPVD1 in two families with early-onset NS and a homozygous missense mutation of ANKFY1 in two siblings with SRNS. GAPVD1 and ANKFY1 interact with the endosomal regulator RAB5. Coimmunoprecipitation assays indicated interaction between GAPVD1 and ANKFY1 proteins, which also colocalized when expressed in HEK293T cells. Silencing either protein diminished the podocyte migration rate. Compared with wild-type GAPVD1 and ANKFY1, the mutated proteins produced upon ectopic expression of GAPVD1 or ANKFY1 bearing the patient-derived mutations exhibited altered binding affinity for active RAB5 and reduced ability to rescue the knockout-induced defect in podocyte migration. Coimmunoprecipitation assays further demonstrated a physical interaction between nephrin and GAPVD1, and immunofluorescence revealed partial colocalization of these proteins in rat glomeruli. The patient-derived GAPVD1 mutations reduced nephrin-GAPVD1 binding affinity. In Drosophila, silencing Gapvd1 impaired endocytosis and caused mistrafficking of the nephrin ortholog. Conclusions Mutations in GAPVD1 and probably in ANKFY1 are novel monogenic causes of NS. The discovery of these genes implicates RAB5 regulation in the pathogenesis of human NS.

Authors with CRIS profile

Tilman Jobst-Schwan

Involved external institutions

Eli and Edythe L. Broad Institute of MIT and Harvard US United States (USA) (US) Harvard University US United States (USA) (US) King Abdulaziz University (KAU) / جامعة الملك عبد العزيز SA Saudi Arabia (SA) University of Washington US United States (USA) (US) Providence Sacred Heart Medical Center and Children's Hospital US United States (USA) (US) Yale University US United States (USA) (US) All India Institute of Medical Sciences IN India (IN)

How to cite

APA:

Hermle, T., Schneider, R., Schapiro, D., Braun, D.A., Van Der Ven, A.T., Warejko, J.K.,... Hildebrandt, F. (2018). GAPVD1 and ANKFY1 mutations implicate RAB5 regulation in nephrotic syndrome. Journal of the American Society of Nephrology, 29(8), 2123-2138. https://doi.org/10.1681/ASN.2017121312

MLA:

Hermle, Tobias, et al. "GAPVD1 and ANKFY1 mutations implicate RAB5 regulation in nephrotic syndrome." Journal of the American Society of Nephrology 29.8 (2018): 2123-2138.

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