FAT1 mutations cause a glomerulotubular nephropathy.

TitleFAT1 mutations cause a glomerulotubular nephropathy.
Publication TypeJournal Article
Year of Publication2016
AuthorsGee, HYung, Sadowski, CE, Aggarwal, PK, Porath, JD, Yakulov, TA, Schueler, M, Lovric, S, Ashraf, S, Braun, DA, Halbritter, J, Fang, H, Airik, R, Vega-Warner, V, Cho, KJee, Chan, TA, Morris, LGT, ffrench-Constant, C, Allen, N, McNeill, H, Büscher, R, Kyrieleis, H, Wallot, M, Gaspert, A, Kistler, T, Milford, DV, Saleem, MA, Keng, WTeik, Alexander, SI, Valentini, RP, Licht, C, Teh, JC, Bogdanovic, R, Koziell, A, Bierzynska, A, Soliman, NA, Otto, EA, Lifton, RP, Holzman, LB, Sibinga, NES, Walz, G, Tufro, A, Hildebrandt, F
JournalNat Commun
Volume7
Pagination10822
Date Published2016 Feb 24
ISSN2041-1723
KeywordsAnimals, Cadherins, cdc42 GTP-Binding Protein, Cell Adhesion, Cell Movement, Dilatation, Pathologic, Fibroblasts, Gene Knockdown Techniques, Hematuria, Humans, Kidney Tubules, Lissencephaly, Mice, Mutation, Nephrotic Syndrome, Podocytes, rac1 GTP-Binding Protein, Syndrome, Zebrafish, Zebrafish Proteins
Abstract

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.

DOI10.1038/ncomms10822
Alternate JournalNat Commun
PubMed ID26905694
PubMed Central IDPMC4770090
Grant ListUM1 HG006504 / HG / NHGRI NIH HHS / United States
DK068306 / DK / NIDDK NIH HHS / United States
R01 DK080751 / DK / NIDDK NIH HHS / United States
DK076683 / DK / NIDDK NIH HHS / United States
R01 HL104518 / HL / NHLBI NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
K08 DE024774 / DE / NIDCR NIH HHS / United States
HL104518 / HL / NHLBI NIH HHS / United States
MR/J006742/1 / / Medical Research Council / United Kingdom
R01 DK076683 / DK / NIDDK NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 DK068306 / DK / NIDDK NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
DK090917 / DK / NIDDK NIH HHS / United States
RC4 DK090917 / DK / NIDDK NIH HHS / United States
R01 DK059333 / DK / NIDDK NIH HHS / United States
DK059333 / DK / NIDDK NIH HHS / United States