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 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

Molecular Analysis of Congenital Hypothyroidism in Saudi Arabia:SLC26A7 Mutation Is a Novel Defect in Thyroid Dyshormonogenesis

Abstract Context Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, affecting one in 3000 to 4000 newborns. Since the introduction of a newborn screening program in 1988, more than 300 cases have been identified. The underlying genetic defects have not been systematically studied. Objective To identify the mutation spectrum of CH-causing genes. Methods Fifty-five patients from 47 families were studied by next-generation exome sequencing. Results Mutations were identified in 52.7% of patients (29 of 55) in the following 11 genes: TG, TPO, DUOX2, SLC26A4, SLC26A7, TSHB, TSHR, NKX2-1, PAX8, CDCA8, and HOXB3. Among 30 patients with thyroid dyshormonogenesis, biallelic TG mutations were found in 12 patients (40%), followed by biallelic mutations in TPO (6.7%), SLC26A7 (6.7%), and DUOX2 (3.3%). Monoallelic SLC26A4 mutations were found in two patients, one of them coexisting with two tandem biallelic deletions in SLC26A7. In 25 patients with thyroid dysgenesis, biallelic mutations in TSHR were found in six patients (24%). Biallelic mutations in TSHB, PAX 8, NKX2-1, or HOXB3 were found once in four different patients. A monoallelic CDCA8 mutation was found in one patient. Most mutations were novel, including three TG, two TSHR, and one each in DUOX2, TPO, SLC26A7, TSHB, NKX2-1, PAX8, CDCA8, and HOXB3. SLC26A7 and HOXB3 were novel genes associated with thyroid dyshormonogenesis and dysgenesis, respectively. Conclusions TG and TSHR mutations are the most common genetic defects in Saudi patients with CH. The prevalence of other disease-causing mutations is low, reflecting the consanguineous nature of the population. SLC26A7 mutations appear to be associated with thyroid dyshormonogenesis. </jats:sec

Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia:Novel Mutations in PHEX and SLC34A3

Hereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed.Clinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions.Genetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887-22,395,767del (179880 bp deletion including exon 16-22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families.This is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood

Clinical and laboratory characteristics of children with de novo or inherited <i>PHEX</i> mutations.

<p>Clinical and laboratory characteristics of children with de novo or inherited <i>PHEX</i> mutations.</p

Summary of clinical and laboratory findings in patients with hereditary hypophosphatemia.

<p>Summary of clinical and laboratory findings in patients with hereditary hypophosphatemia.</p

Characterization of a large deletion of <i>PHEX</i> in patient V-3.

<p>(A) Genechip cytogenetics array results. The top is showing weighted log2 ratios plot showing a normal copy number state for the X chromosome. The deletion is indicated by a dark bar and enclosed in the black lines. More than 70 SNP probes are present in the deleted region and indicated by an arrow. (B) Schematic representation of 179,880 bp deletion of <i>PHEX</i> and <i>ZNF645</i>. The 5’ breakpoint is located in the intron 15 of <i>PHEX</i> and 7 kb from exon 15. The 3’ breakpoint point is 103 kb from <i>ZNF645</i>, resulting in the deletion of exon 16–22 of PHEX and entire <i>ZNF645</i>. The 5’ and 3’ undeleted nucleotide sequences are highlightted in bold. Deletion analysis is based on GRCh37/hg19. (C) Electropherogram of the breaking point. The DNA fragment was amplified by PCR using primers flanking the 5’ and 3’ deletion point. The breakpoint is indicated by an arrow.</p

Sequence analysis of <i>PHEX</i> in patients with hereditary hypophosphatemia.

<p>(A) Five novel <i>PHEX</i> mutations. c.983_987dupCTACC (patient II-3 and her mother) and c.436+1G>T (patient IX-3 and his mother) are inherited mutations from mother; c.1586+2T>G (patinet IV-3), c.1206delA (patient XV-3), and c.1217G>T (patientVI-3) are de novo mutations not present in parents. The c.1586+2T>G results in exon 14 skipping. (B) Six previously reported <i>PHEX</i> mutations. c.1645C>T, c. 187+1G>T, and c.2104C>T are de novo mutations. c.1601C>T, c.2239C>T, and c.1404+1del G are inherited mutations transmitted from mother. Mutation is indicated by an arrow.</p

Sequence analysis of <i>SLC34A3</i> in a patient with hereditary hypophosphatemia.

<p>A novel heterozygous mutation c.1639-1652del14 is present in the mother, patient, and his sister. A novel heterozygous splice donor site mutation c.1335+2T>A is present in the father, patient, and his sister. Compound heterozygous <i>SLC34A3</i> mutations are carried by both patient and his sister. Mutation is indicated by an arrow.</p

<i>In silico</i> prediction of single nucleotide variations in the <i>PHEX</i> gene.

<p><i>In silico</i> prediction of single nucleotide variations in the <i>PHEX</i> gene.</p