期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 12, 页码 5179-5189出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI69000
关键词
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资金
- NIH [DK076683, DK086542, DK46073, DK081943, DK090917, DK091405, R01HL090801, EY07042, U54HG006504, S10RR024605]
- Kidney Foundation of Canada and Nephcure Canada
- Nephcure Foundation
- National Research Foundation
- Ministry of Education, Science and Technology [2012R1A6A3A03040212]
- American Heart Association [AHA-0630178N]
- Association Francaise contre les Myopathies [ANR-08GENOPAT-017-01]
- Fondation pour la Recherche Medicale [DMP 2010-11-20-386]
- European Community's 7th Framework program [2012-305608]
- Ruth L. Kirschstein NIH Service Award [GM 007185]
- Kids Kidney Research and Garfield Weston Foundation
- King Abdul-Aziz University
- Fondazione CARIPARO
- National Science Foundation [0919609]
- German Network of mitochondrial disorders [mitoNET 01GM1113C]
- National Center for Research Resources
- Deanship of Scientific Research
- King Abdulaziz University, Jeddah
- National Research Foundation of Korea [2012R1A6A3A03040212] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1330803] Funding Source: National Science Foundation
- Kidney Research UK [RP45/2008] Funding Source: researchfish
- Medical Research Council [G0800571] Funding Source: researchfish
- MRC [G0800571] Funding Source: UKRI
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).
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