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

Shazia Ashraf; Heon Yung Gee; Stephanie Woerner; Letian X. Xie; Virginia Vega-Warner; Svjetlana Lovric; Humphrey Fang; Xuewen Song; Daniel C. Cattran; Carmen Avila-Casado; Andrew D. Paterson; Patrick Nitschké; Christine Bole-Feysot; Pierre Cochat; Julian Esteve-Rudd; Birgit Haberberger; Susan J. Allen; Weibin Zhou; Rannar Airik; Edgar A. Otto; Moumita Barua; Mohamed H. Al-Hamed; Jameela A. Kari; Jonathan Evans; Agnieszka Bierzynska; Moin A. Saleem; Detlef Böckenhauer; Robert Kleta; Sherif El Desoky; Duygu O. Hacihamdioglu; Faysal Gok; Joseph Washburn; Roger C. Wiggins; Murim Choi; Richard P. Lifton; Shawn Levy; Zhe Han; Leonardo Salviati; Holger Prokisch; David S. Williams; Martin Pollak; Catherine F. Clarke; York Pei; Corinne Antignac; Friedhelm Hildebrandt

doi:10.1172/JCI69000

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

Shazia Ashraf, Heon Yung Gee, Stephanie Woerner, Letian X. Xie, Virginia Vega-Warner, Svjetlana Lovric, Humphrey Fang, Xuewen Song, Daniel C. Cattran, Carmen Avila-Casado, Andrew D. Paterson, Patrick Nitschké, Christine Bole-Feysot, Pierre Cochat, Julian Esteve-Rudd, Birgit Haberberger, Susan J. Allen, Weibin Zhou, Rannar Airik, Edgar A. OttoMoumita Barua, Mohamed H. Al-Hamed, Jameela A. Kari, Jonathan Evans, Agnieszka Bierzynska, Moin A. Saleem, Detlef Böckenhauer, Robert Kleta, Sherif El Desoky, Duygu O. Hacihamdioglu, Faysal Gok, Joseph Washburn, Roger C. Wiggins, Murim Choi, Richard P. Lifton, Shawn Levy, Zhe Han, Leonardo Salviati, Holger Prokisch, David S. Williams, Martin Pollak, Catherine F. Clarke, York Pei, Corinne Antignac, Friedhelm Hildebrandt

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Abstract

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 Q₁₀ (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 CoQ10 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 CoQ₁₀ addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ₁₀ treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ₁₀ biosynthesis may be treatable with CoQ₁₀.

Original language	English
Pages (from-to)	5179-5189
Number of pages	11
Journal	Journal of Clinical Investigation
Volume	123
Issue number	12
DOIs	https://doi.org/10.1172/JCI69000
State	Published - 2 Dec 2013
Externally published	Yes

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Ashraf, S., Gee, H. Y., Woerner, S., Xie, L. X., Vega-Warner, V., Lovric, S., Fang, H., Song, X., Cattran, D. C., Avila-Casado, C., Paterson, A. D., Nitschké, P., Bole-Feysot, C., Cochat, P., Esteve-Rudd, J., Haberberger, B., Allen, S. J., Zhou, W., Airik, R., ... Hildebrandt, F. (2013). ADCK4 mutations promote steroid-Resistant nephrotic syndrome through CoQ10 biosynthesis disruption. Journal of Clinical Investigation, 123(12), 5179-5189. https://doi.org/10.1172/JCI69000

@article{28490b2cf7154009ac61d22d0a5558c7,

title = "ADCK4 mutations promote steroid-Resistant nephrotic syndrome through CoQ10 biosynthesis disruption",

abstract = "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 Q10 (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 CoQ10 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 CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.",

author = "Shazia Ashraf and Gee, {Heon Yung} and Stephanie Woerner and Xie, {Letian X.} and Virginia Vega-Warner and Svjetlana Lovric and Humphrey Fang and Xuewen Song and Cattran, {Daniel C.} and Carmen Avila-Casado and Paterson, {Andrew D.} and Patrick Nitschk{\'e} and Christine Bole-Feysot and Pierre Cochat and Julian Esteve-Rudd and Birgit Haberberger and Allen, {Susan J.} and Weibin Zhou and Rannar Airik and Otto, {Edgar A.} and Moumita Barua and Al-Hamed, {Mohamed H.} and Kari, {Jameela A.} and Jonathan Evans and Agnieszka Bierzynska and Saleem, {Moin A.} and Detlef B{\"o}ckenhauer and Robert Kleta and Desoky, {Sherif El} and Hacihamdioglu, {Duygu O.} and Faysal Gok and Joseph Washburn and Wiggins, {Roger C.} and Murim Choi and Lifton, {Richard P.} and Shawn Levy and Zhe Han and Leonardo Salviati and Holger Prokisch and Williams, {David S.} and Martin Pollak and Clarke, {Catherine F.} and York Pei and Corinne Antignac and Friedhelm Hildebrandt",

year = "2013",

month = dec,

day = "2",

doi = "10.1172/JCI69000",

language = "English",

volume = "123",

pages = "5179--5189",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "12",

}

Ashraf, S, Gee, HY, Woerner, S, Xie, LX, Vega-Warner, V, Lovric, S, Fang, H, Song, X, Cattran, DC, Avila-Casado, C, Paterson, AD, Nitschké, P, Bole-Feysot, C, Cochat, P, Esteve-Rudd, J, Haberberger, B, Allen, SJ, Zhou, W, Airik, R, Otto, EA, Barua, M, Al-Hamed, MH, Kari, JA, Evans, J, Bierzynska, A, Saleem, MA, Böckenhauer, D, Kleta, R, Desoky, SE, Hacihamdioglu, DO, Gok, F, Washburn, J, Wiggins, RC, Choi, M, Lifton, RP, Levy, S, Han, Z, Salviati, L, Prokisch, H, Williams, DS, Pollak, M, Clarke, CF, Pei, Y, Antignac, C & Hildebrandt, F 2013, 'ADCK4 mutations promote steroid-Resistant nephrotic syndrome through CoQ10 biosynthesis disruption', Journal of Clinical Investigation, vol. 123, no. 12, pp. 5179-5189. https://doi.org/10.1172/JCI69000

TY - JOUR

T1 - ADCK4 mutations promote steroid-Resistant nephrotic syndrome through CoQ10 biosynthesis disruption

AU - Ashraf, Shazia

AU - Gee, Heon Yung

AU - Woerner, Stephanie

AU - Xie, Letian X.

AU - Vega-Warner, Virginia

AU - Lovric, Svjetlana

AU - Fang, Humphrey

AU - Song, Xuewen

AU - Cattran, Daniel C.

AU - Avila-Casado, Carmen

AU - Paterson, Andrew D.

AU - Nitschké, Patrick

AU - Bole-Feysot, Christine

AU - Cochat, Pierre

AU - Esteve-Rudd, Julian

AU - Haberberger, Birgit

AU - Allen, Susan J.

AU - Zhou, Weibin

AU - Airik, Rannar

AU - Otto, Edgar A.

AU - Barua, Moumita

AU - Al-Hamed, Mohamed H.

AU - Kari, Jameela A.

AU - Evans, Jonathan

AU - Bierzynska, Agnieszka

AU - Saleem, Moin A.

AU - Böckenhauer, Detlef

AU - Kleta, Robert

AU - Desoky, Sherif El

AU - Hacihamdioglu, Duygu O.

AU - Gok, Faysal

AU - Washburn, Joseph

AU - Wiggins, Roger C.

AU - Choi, Murim

AU - Lifton, Richard P.

AU - Levy, Shawn

AU - Han, Zhe

AU - Salviati, Leonardo

AU - Prokisch, Holger

AU - Williams, David S.

AU - Pollak, Martin

AU - Clarke, Catherine F.

AU - Pei, York

AU - Antignac, Corinne

AU - Hildebrandt, Friedhelm

PY - 2013/12/2

Y1 - 2013/12/2

N2 - 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 Q10 (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 CoQ10 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 CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.

AB - 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 Q10 (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 CoQ10 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 CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.

UR - http://www.scopus.com/inward/record.url?scp=84890038202&partnerID=8YFLogxK

U2 - 10.1172/JCI69000

DO - 10.1172/JCI69000

M3 - Article

C2 - 24270420

AN - SCOPUS:84890038202

SN - 0021-9738

VL - 123

SP - 5179

EP - 5189

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 12

ER -

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

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