and Mutations Implicate RAB5 Regulation in Nephrotic Syndrome.

Title and Mutations Implicate RAB5 Regulation in Nephrotic Syndrome.
Publication TypeJournal Article
Year of Publication2018
AuthorsHermle, 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, Desoky, SEl, Kari, JA, Laricchia, KM, Lek, M, Rehm, HL, MacArthur, DG, Mane, S, Lifton, RP, Shril, S, Hildebrandt, F
JournalJ Am Soc Nephrol
Date Published2018 Aug

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 functional significance of two genes and the mutations therein that we discovered through this sequencing and conducted complementary studies in podocyte-like nephrocytes.

RESULTS: We identified conserved, homozygous missense mutations of in two families with early-onset NS and a homozygous missense mutation of 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 or 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 mutations reduced nephrin-GAPVD1 binding affinity. In , silencing impaired endocytosis and caused mistrafficking of the nephrin ortholog.

CONCLUSIONS: Mutations in and probably in are novel monogenic causes of NS. The discovery of these genes implicates RAB5 regulation in the pathogenesis of human NS.

Alternate JournalJ. Am. Soc. Nephrol.
PubMed ID29959197
PubMed Central IDPMC6065084
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
R01 DK076683 / DK / NIDDK NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
T32 DK007726 / DK / NIDDK NIH HHS / United States