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 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 .

Steroid-resistant nephrotic syndrome caused by co-inheritance of mutations at <i>NPHS1</i> and <i>ADCK4</i> genes in two Chinese siblings

“…However, the onset ages of the siblings are 9-year and 2-year old respectively, they are childhood and infantile nephrotic syndrome but not CNS. The onset ages of SRNS caused by ADCK4 mutation are generally late that range from 7 ~ 21 years old when patients develope ESRD to 7 ~ 23 years old when they were found with a renal pathology of FSGS (16). ADCK4 is thought to be an important differential diagnosis to consider in case of adolescent-onset multidrug-resistant proteinuria with FSGS on biopsy (15).…”

“…Furthermore, it has recently been shown that mutations in NPHS1 also account for a nonnegligible proportion of infantile, childhood and adult-onset SRNS cases (12)(13)(14). ADCK4 gene, which located on chromosome 19q13.2 and encodes the aarF domain containing kinase 4, is now well-known as a single-gene cause of SRNS (15)(16)(17).…”

ADCK4-Associated Glomerulopathy Causes Adolescence-Onset FSGS

“…2 Recently, recessive mutations in ADCK4 (AarF Domain Containing Kinase-4) have been added to this list as a novel cause of steroid-resistant nephrotic syndrome (SRNS). 6 ADCK4 interacts with components of the CoQ 10 biosynthesis pathway, and patients with ADCK4 mutations have reduced cellular CoQ 10 content. 6,7 The selective glomerular phenotype of patients with ADCK4 mutations may be the result of relative enrichment of ADCK4 and lacking expression of the related protein ADCK3 in podocytes, whereas ADCK3 expression exceeds that of ADCK4 in most other body tissues.…”

“…6 ADCK4 interacts with components of the CoQ 10 biosynthesis pathway, and patients with ADCK4 mutations have reduced cellular CoQ 10 content. 6,7 The selective glomerular phenotype of patients with ADCK4 mutations may be the result of relative enrichment of ADCK4 and lacking expression of the related protein ADCK3 in podocytes, whereas ADCK3 expression exceeds that of ADCK4 in most other body tissues. 6 We identified a new patient cohort with ADCK4 glomerulopathy among 534 consecutive SRNS cases.…”

Coenzyme Q supplementation or Over-Expression of the Yeast Coq8 Putative Kinase Stabilizes Multi-Subunit Coq Polypeptide Complexes in Yeast Coq Null Mutants

“…ADCK4 (a human homolog of yeast Coq8) was shown to interact with COQ6 and COQ7 polypeptides in podocyte cell cultures [78]. Although we have not detected Coq8 in direct association with any of the yeast Coq polypeptides, it is tempting to speculate that human ADCK4 may recognize COQ6 and COQ7 as potential substrates for phosphorylation.…”