GAPVD1 and ANKFY1 Mutations Implicate RAB5 Regulation in Nephrotic Syndrome
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GAPVD1 and ANKFY1 Mutations Implicate RAB5 Regulation in Nephrotic Syndrome. / Hermle, Tobias; Schneider, Ronen; Schapiro, David; Braun, Daniela A; van der Ven, Amelie T; Warejko, Jillian K; Daga, Ankana; Widmeier, Eugen; Nakayama, Makiko; Jobst-Schwan, Tilman; Majmundar, Amar J; Ashraf, Shazia; Rao, Jia; Finn, Laura S; Tasic, Velibor; Hernandez, Joel D; Bagga, Arvind; Jalalah, Sawsan M; El Desoky, Sherif; Kari, Jameela A; Laricchia, Kristen M; Lek, Monkol; Rehm, Heidi L; MacArthur, Daniel G; Mane, Shrikant; Lifton, Richard P; Shril, Shirlee; Hildebrandt, Friedhelm.
in: J AM SOC NEPHROL, Jahrgang 29, Nr. 8, 08.2018, S. 2123-2138.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - GAPVD1 and ANKFY1 Mutations Implicate RAB5 Regulation in Nephrotic Syndrome
AU - Hermle, Tobias
AU - Schneider, Ronen
AU - Schapiro, David
AU - Braun, Daniela A
AU - van der Ven, Amelie T
AU - Warejko, Jillian K
AU - Daga, Ankana
AU - Widmeier, Eugen
AU - Nakayama, Makiko
AU - Jobst-Schwan, Tilman
AU - Majmundar, Amar J
AU - Ashraf, Shazia
AU - Rao, Jia
AU - Finn, Laura S
AU - Tasic, Velibor
AU - Hernandez, Joel D
AU - Bagga, Arvind
AU - Jalalah, Sawsan M
AU - El Desoky, Sherif
AU - Kari, Jameela A
AU - Laricchia, Kristen M
AU - Lek, Monkol
AU - Rehm, Heidi L
AU - MacArthur, Daniel G
AU - Mane, Shrikant
AU - Lifton, Richard P
AU - Shril, Shirlee
AU - Hildebrandt, Friedhelm
N1 - Copyright © 2018 by the American Society of Nephrology.
PY - 2018/8
Y1 - 2018/8
N2 - 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.
AB - 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.
KW - Animals
KW - Cell Movement/genetics
KW - Cells, Cultured
KW - Cohort Studies
KW - Disease Progression
KW - Drosophila melanogaster
KW - Female
KW - Gene Expression Regulation
KW - Genetic Predisposition to Disease
KW - Humans
KW - Male
KW - Mass Screening/methods
KW - Membrane Proteins/genetics
KW - Mutation, Missense
KW - Nephrotic Syndrome/genetics
KW - Pedigree
KW - Podocytes/metabolism
KW - RNA, Small Interfering/genetics
KW - Real-Time Polymerase Chain Reaction/methods
KW - Renal Insufficiency, Chronic/genetics
KW - Whole Exome Sequencing
KW - rab5 GTP-Binding Proteins/genetics
U2 - 10.1681/ASN.2017121312
DO - 10.1681/ASN.2017121312
M3 - SCORING: Journal article
C2 - 29959197
VL - 29
SP - 2123
EP - 2138
JO - J AM SOC NEPHROL
JF - J AM SOC NEPHROL
SN - 1046-6673
IS - 8
ER -
