ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

被引：201

作者：

Gee, Heon Yung ^{[1
]}

Saisawat, Pawaree ^{[2
]}

Ashraf, Shazia ^{[1
]}

Hurd, Toby W. ^{[3
]}

Vega-Warner, Virginia ^{[2
]}

Fang, Humphrey ^{[1
]}

Beck, Bodo B. ^{[4
]}

Gribouval, Olivier ^{[5
,6
,7
]}

Zhou, Weibin ^{[2
]}

Diaz, Katrina A. ^{[2
]}

Natarajan, Sivakumar ^{[2
]}

Wiggins, Roger C. ^{[8
]}

Lovric, Svjetlana ^{[1
]}

Chernin, Gil ^{[2
]}

Schoeb, Dominik S. ^{[2
]}

Ovunc, Bugsu ^{[2
]}

Frishberg, Yaacov ^{[9
]}

Soliman, Neveen A. ^{[10
,11
]}

Fathy, Hanan M. ^{[12
]}

Goebel, Heike ^{[13
]}

Hoefele, Julia ^{[14
]}

Weber, Lutz T. ^{[15
]}

Innis, Jeffrey W. ^{[2
,16
]}

Faul, Christian ^{[17
]}

Han, Zhe ^{[18
]}

Washburn, Joseph ^{[19
]}

Antignac, Corinne ^{[5
,6
,7
]}

Levy, Shawn ^{[20
]}

Otto, Edgar A. ^{[2
]}

Hildebrandt, Friedhelm ^{[1
,21
]}

机构：

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

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

[3] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

[4] Univ Cologne, Inst Human Genet, D-50931 Cologne, Germany

[5] INSERM, U983, Paris, France

[6] Hop Necker Enfants Malad, AP HP, Serv Genet, Paris, France

[7] Univ Paris 05, Sorbonne Paris Cite, Inst Imagine, Paris, France

[8] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[9] Shaare Zedek Med Ctr, Div Pediat Nephrol, Jerusalem, Israel

[10] Cairo Univ, Kasr Al Ainy Sch Med, Dept Pediat, Cairo, Egypt

[11] EGORD, Cairo, Egypt

[12] Univ Alexandria, Pediat Nephrol Unit, Alexandria, Egypt

[13] Univ Hosp Cologne, Inst Pathol, Cologne, Germany

[14] Ctr Human Genet & Lab Med Dr Klein Dr Rost & Coll, Martinsried, Germany

[15] Univ Munich, Univ Childrens Hosp, Munich, Germany

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

[17] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA

[18] Univ Michigan, Dept Internal Med Mol Med & Genet, Ann Arbor, MI 48109 USA

[19] Univ Michigan, Ctr Canc, Ann Arbor, MI 48109 USA

[20] HudsonAlpha Inst Biotechnol, Huntsville, AL USA

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

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2013年 / 123卷 / 08期

关键词：

GLOMERULAR PROTEIN; KIDNEY; PODOCYTES; CAPTURE; PODOCIN; ACTIN; GENE; MECHANISMS; SPECTRUM; NEPHRIN;

D O I：

10.1172/JCI69134

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.

引用

页码：3243 / 3253

页数：11

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