Mutation of SGK3, a novel regulator of renal phosphate transport, causes autosomal dominant hypophosphatemic rickets.

CONTEXT: Hypophosphataemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in the PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1 or SLC34A3. OBJECTIVE: A large kindred with 5 HR patients were recruited with dominant inheritance. The study was undertaken to investigate underlying genetic defects in the HR patients. DESIGN: Patients and their family members were initially analyzed for PHEX and FGF23 mutations by PCR-sequencing and copy number analysis. Exome sequencing was subsequently performed to identify novel candidate genes. RESULTS: PHEX and FGF23 mutations were not detected in the patients. No copy number variation was observed in the genome by CytoScan HD Array analysis. Mutations in the DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1 or SLC34A3 were not found as well by exome sequencing. A novel c.979-96 T>A mutation in the SGK3 gene was found to be strictly segregated with patients in a heterozygous pattern and was not present in the normal family members. The mutation is located 1 bp downstream of highly conserved adenosine branch point, resulted in exon 13 skipping and in-frame deletion of 29 amino acids, which is part of protein kinase domain and contains Thr-320 phosphorylation site required for its activation. Protein tertiary structure modelling showed significant structural change in the protein kinase domain following the deletion. CONCLUSIONS: The c.979-96 T>A splice mutation in the SGK3 gene causes exon 13 skipping and deletion of 29 amino acids in the protein kinase domain. The SGK3 mutation may cause autosomal dominant HR.