KANK deficiency leads to pod ocyte dysfunction and nephrotic syndrome

被引：160

作者：

Gee, Heon Yung ^{[1
]}

Zhang, Fujian ^{[2
,3
]}

Ashraf, Shazia ^{[1
]}

Kohl, Stefan ^{[1
]}

Sadowski, Carolin E. ^{[1
]}

Vega-Warner, Virginia ^{[4
]}

Zhou, Weibin ^{[4
]}

Lovric, Svjetlana ^{[1
]}

Fang, Humphrey ^{[1
]}

Nettleton, Margaret ^{[2
]}

Zhu, Jun-yi ^{[2
]}

Hoefele, Julia ^{[5
]}

Weber, Lutz T. ^{[6
]}

Podracka, Ludmila ^{[7
,8
]}

Boor, Andrej ^{[9
]}

Fehrenbach, Henry ^{[10
]}

Innis, Jeffrey W. ^{[4
,11
]}

Washburn, Joseph ^{[12
]}

Levy, Shawn ^{[13
]}

Lifton, Richard P. ^{[14
,15
]}

Otto, Edgar A. ^{[4
]}

Han, Zhe ^{[2
]}

Hildebrandt, Friedhelm ^{[1
,15
]}

机构：

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

[2] Childrens Natl Med Ctr, Ctr Canc & Immunol Res, Washington, DC 20010 USA

[3] Southern Med Univ, Nanfang Hosp, Div Nephrol, Guangzhou, Guangdong, Peoples R China

[4] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA

[5] Ctr Human Genet & Lab Diagnost, Martinsried, Germany

[6] Univ Hosp Cologne, Childrens & Adolescents Hosp, Pediat Nephrol, Cologne, Germany

[7] Comenius Univ, Fac Med, Dept Pediat 1, Bratislava, Slovakia

[8] Childrens Univ Hosp, Bratislava, Slovakia

[9] Safarik Univ, Fac Med, Dept Pathol, Kosice, Slovakia

[10] Childrens Hosp, Dept Pediat Nephrol, Memmingen, Germany

[11] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA

[12] Univ Michigan, Biomed Res Core Facil, Ann Arbor, MI 48109 USA

[13] HudsonAlpha Inst Biotechnol, Huntsville, AL USA

[14] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA

[15] Howard Hughes Med Inst, Chevy Chase, MD USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2015年 / 125卷 / 06期

关键词：

FOCAL SEGMENTAL GLOMERULOSCLEROSIS; RHO GTPASES; PODOCYTE INJURY; SLIT DIAPHRAGM; IN-VIVO; MUTATIONS; PROTEIN; RAC1; CELL; NEPHROCYTES;

D O I：

10.1172/JCI79504

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of progressive renal function decline and affects millions of people. In a recent study, 30% of SRNS cases evaluated were the result of monogenic mutations in 1 of 27 different genes. Here, using homozygosity mapping and whole-exome sequencing, we identified recessive mutations in kidney ankyrin repeat-containing protein 1 (KANK1), KANK2, and KANK4 in individuals with nephrotic syndrome. In an independent functional genetic screen of Drosophila cardiac nephrocytes, which are equivalents of mammalian podocytes, we determined that the Drosophila KANK homolog (dKank) is essential for nephrocyte function. RNAi-mediated knockdown of dKank in nephrocytes disrupted slit diaphragm filtration structures and lacuna channel structures. In rats, KANK1, KANK2, and KANK4 all localized to podocytes in glomeruli, and KANK1 partially colocalizeci with synaptopodin. Knockdown of kank2 in zebrafish recapitulated a nephrotic syndrome phenotype, resulting in proteinuria and podocyte foot process effacement. In rat glomeruli and cultured human podocytes, KANK2 interacted with ARHGDIA, a known regulator of RHO GTPases in podocytes that is dysfunctional in some types of nephrotic syndrome. Knockdown of KANK2 in cultured podocytes increased active GTP-bound RHOA and decreased migration. Together, these data suggest that KANK family genes play evolutionarily conserved roles in podocyte function, likely through regulating RHO GTPase signaling.

引用

页码：2375 / 2384

页数：10

共 34 条

[21] A novel ankyrin repeat-containing gene (Kank) located at 9p24 is a growth suppressor of renal cell carcinoma [J].