ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption

被引：255

作者：

Ashraf, Shazia ^{[1
]}

Gee, Heon Yung ^{[1
]}

Woerner, Stephanie ^{[2
,3
]}

Xie, Letian X. ^{[4
,5
]}

Vega-Warner, Virginia ^{[6
]}

Lovric, Svjetlana ^{[1
]}

Fang, Humphrey ^{[1
]}

Song, Xuewen ^{[7
,8
]}

Cattran, Daniel C. ^{[7
,8
]}

Avila-Casado, Carmen ^{[9
]}

Paterson, Andrew D. ^{[10
]}

Nitschke, Patrick ^{[11
]}

Bole-Feysot, Christine ^{[12
]}

Cochat, Pierre ^{[13
]}

Esteve-Rudd, Julian ^{[14
]}

Haberberger, Birgit ^{[15
,16
]}

Allen, Susan J. ^{[6
]}

Zhou, Weibin ^{[6
]}

Airik, Rannar ^{[1
]}

Otto, Edgar A. ^{[6
]}

Barua, Moumita ^{[17
]}

Al-Hamed, Mohamed H. ^{[18
]}

Kari, Jameela A. ^{[19
]}

Evans, Jonathan ^{[20
]}

Bierzynska, Agnieszka ^{[21
]}

Saleem, Moin A. ^{[21
]}

Boeckenhauer, Detlef ^{[22
]}

Kleta, Robert ^{[22
]}

El Desoky, Sherif ^{[19
]}

Hacihamdioglu, Duygu O. ^{[23
]}

Gok, Faysal ^{[23
]}

Washburn, Joseph ^{[24
]}

Wiggins, Roger C. ^{[25
,26
]}

Choi, Murim ^{[27
,28
]}

Lifton, Richard P. ^{[27
,28
]}

Levy, Shawn ^{[29
]}

Han, Zhe ^{[30
]}

Salviati, Leonardo ^{[31
,32
]}

Prokisch, Holger ^{[15
,16
]}

Williams, David S. ^{[14
]}

Pollak, Martin ^{[13
]}

Clarke, Catherine F. ^{[4
,5
]}

Pei, York ^{[7
,8
]}

Antignac, Corinne ^{[2
,3
,33
]}

Hildebrandt, Friedhelm ^{[1
,34
,35
]}

机构：

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

[2] Hop Necker Enfants Malad, INSERM, U983, F-75015 Paris, France

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

[4] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90024 USA

[5] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA

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

[7] Univ Hlth Network, Div Nephrol, Toronto, ON M5G 2N2, Canada

[8] Univ Toronto, Toronto, ON M5G 2N2, Canada

[9] Univ Hlth Network, Dept Pathol, Toronto, ON M5G 2N2, Canada

[10] Hosp Sick Children, Program Genom Biol, Toronto, ON M5G 1X8, Canada

[11] Univ Paris 05, Bioinformat Plateform, Paris, France

[12] Univ Paris 05, Imagine Inst, Genom Plateform, Paris, France

[13] Hosp Civils Lyon, Hop Femme Mere Enfant, Ctr Reference Malad Renales Rares, Serv Nephrol & Rhumatol Pediat, Bron, France

[14] Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90024 USA

[15] Helmholtz Zentrum Munich, Inst Human Genet, Neuherberg, Germany

[16] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-80290 Munich, Germany

[17] Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA

[18] Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[19] King Abdulaziz Univ, Dept Pediat, Jeddah 21413, Saudi Arabia

[20] Univ Nottingham Hosp, Nottingham NG7 2UH, England

[21] Univ Bristol, Childrens & Acad Renal Unit, Bristol, Avon, England

[22] Great Ormond St Hosp Sick Children, UCL Inst Child Hlth & Paediat Nephrol, London, England

[23] Gulhane Mil Med Acad, Sch Med, Dept Pediat Nephrol & Rheumatol, Ankara, Turkey

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

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

[26] Univ Michigan, Dept Otolaryngol, Ann Arbor, MI 48109 USA

[27] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, New Haven, CT 06510 USA

[28] Yale Univ, Sch Med, Yale Ctr Mendelian Genom, New Haven, CT 06510 USA

[29] HudsonAlpha Inst Biotechnol, Huntsville, CT USA

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

[31] Univ Padua, Dept Woman & Child Hlth, Padua, Italy

[32] Ist Ric Pediat Citta Speranza, Padua, Italy

[33] Hop Necker Enfants Malad, Assistance Publ Hop Paris, Dept Genet, F-75015 Paris, France

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

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

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2013年 / 123卷 / 12期

基金：

新加坡国家研究基金会; 美国国家科学基金会;

关键词：

COENZYME Q(10) DEFICIENCY; COLLAPSING GLOMERULOPATHY; SACCHAROMYCES-CEREVISIAE; UBIQUINONE DEFICIENCY; CEREBELLAR-ATAXIA; KIDNEY-DISEASES; COQ2; NEPHROPATHY; NEPHROCYTES; CILIOPATHY;

D O I：

10.1172/JCI69000

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：

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q(10) (CoQ(10)) biosynthesis. Mutations in ADCK4 resulted in reduced COQ(10). levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ(10) biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ(10) addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ(10) treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ(10) biosynthesis may be treatable with CoQ(10).

引用

页码：5179 / 5189

页数：11

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