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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.

Summary: Autosomal-dominant polycystic kidney disease (ADPKD) is the most common Mendelian disorder of the kidney and accounts for approximately 5% of end-stage renal disease in developed countries. It is characterized by focal and sporadic development of renal cysts that increase in number and size with age. Mutations of 2 genes (ie, PKD1 and PKD2) account for most of the cases. Although the clinical manifestations of both gene types overlap completely, PKD1 is associated with more severe disease than PKD2, with bigger kidneys and earlier onset of end-stage renal disease. In general, the diagnosis of ADPKD is commonly made by renal ultrasonography. Age-dependent ultrasound criteria have been established for both diagnosis and disease exclusion in subjects at risk of PKD1. However, the utility of these criteria in the clinic setting is unclear because their performance characteristics have not been defined for the milder PKD2 and the gene type for most test subjects is unknown. Recently, highly predictive ultrasound diagnostic criteria have been derived for at-risk subjects of unknown gene type. In addition, molecular genetic testing is now available for the diagnosis of ADPKD, especially in subjects with equivocal imaging results, with a negative or indeterminate family history, or in younger at-risk individuals with a negative ultrasound study being evaluated as potential living-related kidney donor. Here, we review the clinical utilities and limitations of these imaging- and molecular-based diagnostic tests, and outline our approach for the evaluation of individuals suspected to have ADPKD. [ABSTRACT FROM AUTHOR]