title: ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption.
abstract: 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 Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 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.
authors.forename: Shazia
authors.initials: S
authors.lastname: Ashraf
authors.forename: Heon Yung
authors.initials: HY
authors.lastname: Gee
authors.forename: Stephanie
authors.initials: S
authors.lastname: Woerner
authors.forename: Letian X
authors.initials: LX
authors.lastname: Xie
authors.forename: Virginia
authors.initials: V
authors.lastname: Vega-Warner
authors.forename: Svjetlana
authors.initials: S
authors.lastname: Lovric
authors.forename: Humphrey
authors.initials: H
authors.lastname: Fang
authors.forename: Xuewen
authors.initials: X
authors.lastname: Song
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Cattran
authors.forename: Carmen
authors.initials: C
authors.lastname: Avila-Casado
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschké
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.forename: Pierre
authors.initials: P
authors.lastname: Cochat
authors.forename: Julian
authors.initials: J
authors.lastname: Esteve-Rudd
authors.forename: Birgit
authors.initials: B
authors.lastname: Haberberger
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Allen
authors.forename: Weibin
authors.initials: W
authors.lastname: Zhou
authors.forename: Rannar
authors.initials: R
authors.lastname: Airik
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: Moumita
authors.initials: M
authors.lastname: Barua
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Al-Hamed
authors.forename: Jameela A
authors.initials: JA
authors.lastname: Kari
authors.forename: Jonathan
authors.initials: J
authors.lastname: Evans
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bierzynska
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.forename: Detlef
authors.initials: D
authors.lastname: Böckenhauer
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.forename: Sherif
authors.initials: S
authors.lastname: El Desoky
authors.forename: Duygu O
authors.initials: DO
authors.lastname: Hacihamdioglu
authors.forename: Faysal
authors.initials: F
authors.lastname: Gok
authors.forename: Joseph
authors.initials: J
authors.lastname: Washburn
authors.forename: Roger C
authors.initials: RC
authors.lastname: Wiggins
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.forename: Zhe
authors.initials: Z
authors.lastname: Han
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.forename: Martin
authors.initials: M
authors.lastname: Pollak
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Clarke
authors.forename: York
authors.initials: Y
authors.lastname: Pei
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000494:pharmacology / Q000627:therapeutic use; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D003241:Consanguinity; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D004351:Drug Resistance; D059472:Exome / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008928:Mitochondria / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation; D009404:Nephrotic Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050199:Podocytes / Q000378:metabolism / Q000648:ultrastructure; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051381:Rats; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000627:therapeutic use; D055815:Young Adult; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000305:Adrenal Cortex Hormones; D029721:Drosophila Proteins; D029961:Zebrafish Proteins; C032165:ubiquinone 6; D014451:Ubiquinone; C586096:COQ8B protein, human; D011494:Protein Kinases; C024989:coenzyme Q10; C030777:ubiquinone 7