FAT1 mutations cause a glomerulotubular nephropathy

被引：97

作者：

Gee, Heon Yung ^{[1
,2
]}

Sadowski, Carolin E. ^{[1
]}

Aggarwal, Pardeep K. ^{[3
]}

Porath, Jonathan D. ^{[1
]}

Yakulov, Toma A. ^{[4
]}

Schueler, Markus ^{[1
]}

Lovric, Svjetlana ^{[1
]}

Ashraf, Shazia ^{[1
]}

Braun, Daniela A. ^{[1
]}

Halbritter, Jan ^{[1
]}

Fang, Humphrey ^{[1
]}

Airik, Rannar ^{[1
]}

Vega-Warner, Virginia ^{[5
]}

Cho, Kyeong Jee ^{[2
]}

Chan, Timothy A. ^{[6
]}

Morris, Luc G. T. ^{[6
]}

Ffrench-Constant, Charles ^{[7
]}

Allen, Nicholas ^{[8
]}

McNeill, Helen ^{[9
]}

Buescher, Rainer ^{[10
]}

Kyrieleis, Henriette ^{[11
]}

Wallot, Michael ^{[11
]}

Gaspert, Ariana ^{[12
]}

Kistler, Thomas ^{[13
]}

Milford, David V. ^{[4
,14
]}

Saleem, Moin A. ^{[15
]}

Keng, Wee Teik ^{[16
]}

Alexander, Stephen I. ^{[17
]}

Valentini, Rudolph P. ^{[18
]}

Licht, Christoph ^{[19
,20
]}

Teh, Jun C. ^{[19
,20
]}

Bogdanovic, Radovan ^{[21
]}

Koziell, Ania ^{[22
]}

Bierzynska, Agnieszka ^{[15
]}

Soliman, Neveen A. ^{[23
,24
]}

Otto, Edgar A. ^{[5
]}

Lifton, Richard P. ^{[25
,26
]}

Holzman, Lawrence B. ^{[27
]}

Sibinga, Nicholas E. S. ^{[28
,29
]}

Walz, Gerd ^{[4
]}

Tufro, Alda ^{[3
]}

Hildebrandt, Friedhelm ^{[1
,26
]}

机构：

[1] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Nephrol, Boston, MA 02115 USA

[2] Yonsei Univ, Coll Med, Brain Korea PLUS Project Med Sci 21, Dept Pharmacol, Seoul 03722, South Korea

[3] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA

[4] Univ Freiburg, Med Ctr, D-79106 Freiburg, Germany

[5] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA

[6] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[7] Univ Edinburgh, Multiple Sclerosis Soc Ctr Translat Res, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland

[8] Cardiff Univ, Sch Biosci, Museum Ave, Cardiff CF10 3AX, S Glam, Wales

[9] Univ Toronto, Mt Sinai Hosp, Dept Mol Genet, Samuel Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada

[10] Univ Hosp Essen, Dept Pediat 2, D-45147 Essen, Germany

[11] Bethanien Hosp, Dept Pediat, D-47441 Moers, Germany

[12] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland

[13] Kantonsspital Winterthur, Div Nephrol, CH-8401 Winterthur, Switzerland

[14] Birmingham Childrens Hosp, Dept Paediat Nephrol, Birmingham B4 6NH, W Midlands, England

[15] Univ Bristol, Childrens & Acad Renal Unit, Bristol BS1 5NB, Avon, England

[16] Hosp Kuala Lumpur, Dept Genet, Kuala Lumpur 50586, Malaysia

[17] Childrens Hosp Westmead, Ctr Kidney Res, Westmead, NSW 2145, Australia

[18] Wayne State Univ, Dept Pediat, Div Pediat Nephrol, Childrens Hosp Michigan, Detroit, MI 48201 USA

[19] Hosp Sick Children, Div Nephrol, Toronto, ON M5G 1X8, Canada

[20] Univ Toronto, Toronto, ON M5G 1X8, Canada

[21] Univ Belgrade, Fac Med, Dept Nephrol, Inst Mother & Child Hlth Care Serbia Dr Vukan Cup, Belgrade 11000, Serbia

[22] Kings Coll London, Fac Life Sci & Med, Div Transplantat Immunol & Mucosal Biol, Dept Expt Immunobiol,Guys Hosp, 5th Floor Tower Wing, London SE1 9RT, England

[23] Cairo Univ, Kasr Al Ainy Sch Med, Dept Pediat, Ctr Pediat Nephrol & Transplantat, Cairo 11562, Egypt

[24] Egyptian Grp Orphan Renal Dis, Cairo 11562, Egypt

[25] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA

[26] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[27] Univ Penn, Perelman Sch Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA

[28] Albert Einstein Coll Med, Wilf Family Cardiovasc Res Inst, Bronx, NY 10461 USA

[29] Albert Einstein Coll Med, Dept Med Cardiol, Bronx, NY 10461 USA

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

美国国家卫生研究院; 新加坡国家研究基金会;

关键词：

NEPHROTIC SYNDROME; GLOMERULAR PROTEIN; LINKAGE ANALYSIS; MICE LACKING; LEADS; DEFICIENCY; PODOCIN; KIDNEY; GENE; EXPRESSION;

D O I：

10.1038/ncomms10822

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：11

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