Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of its pathogenesis. However, the genetic causes of a significant proportion of childhood and adult-onset SRNS are still molecularly unidentified. Here, we combined homozygosity mapping (HM) with whole human exome resequencing (WER) and identified 9 different mutations for both alleles in 14 individuals from 7 non-related families in the ADCK4 (aarF domain containing kinase 4) gene. All mutations segregated with the affected status and were absent from >60 ethnically matched healthy controls. ADCK4 has a high sequence similarity to ADCK3, the ortholog of yeast Abc1/Coq8, which participates in the biosynthesis of coenzyme Q10 (CoQ10). We recapitulated the nephrotic syndrome phenotype in zebrafish upon knockdown of adck4. Interestingly, an affected individual with a homozygous frameshift mutation showed partial remission when treated with the innocuous supplement CoQ10. ADCK4 is strongly expressed in glomerular podocytes, and partially localizes to mitochondria and foot processes of podocytes. By coimmunoprecipitation, we demonstrated that ADCK4 interacts with other members of the CoQ10 biosynthesis pathway, including COQ7 and most importantly, COQ6, a known SRNS protein in human culture podocytes. Knockdown of ADCK4 in cultured podocytes resulted in decreased migratory phenotype, which was reversed by addition of CoQ10 or overexpression of mouse Adck4. We, thus, identified recessive mutations of ADCK4 as causing SRNS in humans. Identification of this SRNScausing gene emphasizes the importance of recognizing individuals with mutations of genes that participate in CoQ10 biosynthesis, because they may represent a treatable form of SRNS.
Exome resequencing reveals ADCK4 mutations as novel causes of steroid-resistant nephrotic syndrome
SALVIATI, LEONARDO;
2013
Abstract
Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of its pathogenesis. However, the genetic causes of a significant proportion of childhood and adult-onset SRNS are still molecularly unidentified. Here, we combined homozygosity mapping (HM) with whole human exome resequencing (WER) and identified 9 different mutations for both alleles in 14 individuals from 7 non-related families in the ADCK4 (aarF domain containing kinase 4) gene. All mutations segregated with the affected status and were absent from >60 ethnically matched healthy controls. ADCK4 has a high sequence similarity to ADCK3, the ortholog of yeast Abc1/Coq8, which participates in the biosynthesis of coenzyme Q10 (CoQ10). We recapitulated the nephrotic syndrome phenotype in zebrafish upon knockdown of adck4. Interestingly, an affected individual with a homozygous frameshift mutation showed partial remission when treated with the innocuous supplement CoQ10. ADCK4 is strongly expressed in glomerular podocytes, and partially localizes to mitochondria and foot processes of podocytes. By coimmunoprecipitation, we demonstrated that ADCK4 interacts with other members of the CoQ10 biosynthesis pathway, including COQ7 and most importantly, COQ6, a known SRNS protein in human culture podocytes. Knockdown of ADCK4 in cultured podocytes resulted in decreased migratory phenotype, which was reversed by addition of CoQ10 or overexpression of mouse Adck4. We, thus, identified recessive mutations of ADCK4 as causing SRNS in humans. Identification of this SRNScausing gene emphasizes the importance of recognizing individuals with mutations of genes that participate in CoQ10 biosynthesis, because they may represent a treatable form of SRNS.Pubblicazioni consigliate
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