Mutation of SGK3, a Novel Regulator of Renal Phosphate Transport, Causes Autosomal Dominant Hypophosphatemic Rickets

Cavalier, Etienne/0000-0003-0947-2226; Shi, Yufei/0000-0002-6999-0191WOS: 000553452200045PubMed: 31821448Context. Hypophosphatemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, or SLC34A3. Objective. A large kindred with 5 HR patients was recruited with dominant inheritance. the study was undertaken to investigate underlying genetic defects in HR patients. Design. Patients and their family members were initially analyzed for PHEX and FGF23 mutations using polymerase chain reaction 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 using CytoScan HD array analysis. Mutations in DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, or SLC34A3 were also not found by exome sequencing. A novel c.979-96 T>A mutation in the SGK3 gene was found to be strictly segregated in a heterozygous pattern in patients and was not present in normal family members. the mutation is located 1 bp downstream of a highly conserved adenosine branch point, resulted in exon 13 skipping and in-frame deletion of 29 amino acids, which is part of the protein kinase domain and contains a Thr-320 phosphorylation site that is 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.KACST Biotech grant [13-MED1765-20]This study is supported by a KACST Biotech grant 13-MED1765-20

Novel CYP27B1 Gene Mutations in Patients with Vitamin D-Dependent Rickets Type 1A

The CYP27B1 gene encodes 25-hydroxyvitamin D-1a-hydroxylase. Mutations of this gene cause vitamin D-dependent rickets type 1A (VDDR-IA, OMIM 264700), which is a rare autosomal recessive disorder. To investigate CYP27B1 mutations, we studied 8 patients from 7 unrelated families. All coding exons and intron-exon boundaries of CYP27B1 gene were amplified by PCR from peripheral leukocyte DNA and subsequently sequenced. Homozygous mutations in the CYP27B1 gene were found in all the patients and heterozygous mutations were present in their normal parents. One novel single nucleotide variation (SNV, c. 1215 T>C, p. R379R in the last nucleotide of exon 7) and three novel mutations were identified:, a splice donor site mutation (c. 1215+2T>A) in intron 7, a 16-bp deletion in exon 6 (c. 1022-1037del16), and a 2-bp deletion in exon 5 (c. 934_935delAC). Both c. 1215 T>C and c. 1215+2T>A were present together in homozygous form in two unrelated patients, and caused exon 7 skipping. However, c. 1215 T>C alone has no effect on pre-mRNA splicing. The skipping of exon 7 resulted in a shift of downstream reading frame and a premature stop codon 57 amino acids from L380 (p. L380Afs*57). The intra-exon deletions of c. 1022-1037del16 and c. 934_935delAC also resulted in a frameshift and the creation of premature stop codons at p. T341Rfs*5, and p. T312Rfs*19, respectively, leading to the functional inactivation of the CYP27B1 gene. Clinically, all the patients required continued calcitriol treatment and the clinical presentations were consistent with the complete loss of vitamin D1a-hydroxylase activity. In conclusion, three novel mutations have been identified. All of them caused frameshift and truncated proteins. The silent c. 1215 T>C SNV has no effect on pre-mRNA splicing and it is likely a novel SNP. The current study further expands the CYP27B1 mutation spectrum

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

peer reviewedCONTEXT: 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

NOVEL VDR MUTATIONS IN PATIENTS WITH VITAMIN D-DEPENDENT RICKETS TYPE 2A: A MILD DISEASE PHENOTYPE CAUSED BY A NOVEL CANONICAL SPLICE-SITE MUTATION

Objective: Vitamin D-dependent rickets type 2A (VDDR2A) is a rare autosomal recessive disorder caused by mutations in the vitamin D receptor gene (VDR), leading to end-organ resistance to 1,25-dihydroxyvitamin D-3 (1,25[OH](2)D-3). The objective of this study was to investigate VDR mutations in 11 patients from 8 TurkishArab families

<i>CYP27B1</i> mutations in Turkish population.

<p><i>CYP27B1</i> mutations in Turkish population.</p

A novel deletion of 2-bp nucleotides in the human <i>CYP27B1</i> gene.

<p>A homozygous deletion of AC nucleotides (c.934_935delAC) in exon 5 was found in a patient from family 7. A heterozygous deletion was found in both of his parents. The deletion results in a frameshift and creates a premature TGA stop codon 19 amino acids downstream from the frameshift (p.T312RfsX19).</p