title: Exome sequencing identifies a novel homozygous mutation in the phosphate transporter SLC34A1 in hypophosphatemia and nephrocalcinosis.
abstract: BACKGROUND
  Two Argentinean siblings (a boy and a girl) from a nonconsanguineous family presented with hypercalcemia, hypercalciuria, hypophosphatemia, low parathyroid hormone (PTH), and nephrocalcinosis.
  
  
  OBJECTIVE
  The goal of this study was to identify genetic causes of the clinical findings in the two siblings.
  
  
  METHODS
  Whole exome sequencing was performed to identify disease-causing mutations in the youngest sibling, and a candidate variant was screened in other family members by Sanger sequencing. In vitro experiments were conducted to determine the effects of the mutation that was identified.
  
  
  METHODS
  Affected siblings (2 y.o. female and 10 y.o male) and their parents were included in the study. Informed consent was obtained for genetic studies.
  
  
  RESULTS
  A novel homozygous mutation in the gene encoding the renal sodium-dependent phosphate transporter SLC34A1 was identified in both siblings (c.1484G>A, p.Arg495His). In vitro studies showed that the p.Arg495His mutation resulted in decreased phosphate uptake when compared to wild-type SLC34A1.
  
  
  CONCLUSIONS
  The homozygous G>A transition that results in the substitution of histidine for arginine at position 495 of the renal sodium-dependent phosphate transporter, SLC34A1, is involved in disease pathogenesis in these patients. Our report of the second family with two mutated SLC34A1 alleles expands the known phenotype of this rare condition.
authors: Department of Molecular and Human Genetics (A.R., D.L., R.G., P.C., B.L.), Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030; Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) (D.B., F.C., H.C., I.B.), CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425FD Buenos Aires, Argentina; Human Genome Sequencing Center (J.T.L., R.G.), Department of Structural and Computational Biology and Molecular Biophysics (J.T.L.), Baylor College of Medicine, Houston, Texas 77030; Unidad de Metabolismo (S.K.), Hospital de Niños Ricardo Gutiérrez, C1425FD Buenos Aires, Argentina; Unidad de Nefrología (J.M.L., G.V.), Hospital de Niños Ricardo Gutiérrez, C1425FD Buenos Aires, Argentina; Howard Hughes Medical Institute (B.L.), Houston, Texas 77030.
authors: Abbhirami
authors: A
authors: Rajagopal
authors: Débora
authors: D
authors: Braslavsky
authors: James T
authors: JT
authors: Lu
authors: Soledad
authors: S
authors: Kleppe
authors: Florencia
authors: F
authors: Clément
authors: Hamilton
authors: H
authors: Cassinelli
authors: David S
authors: DS
authors: Liu
authors: Jose Miguel
authors: JM
authors: Liern
authors: Graciela
authors: G
authors: Vallejo
authors: Ignacio
authors: I
authors: Bergadá
authors: Richard A
authors: RA
authors: Gibbs
authors: Phillipe M
authors: PM
authors: Campeau
authors: Brendan H
authors: BH
authors: Lee
mesh_terms: D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics; D053565:Hypercalciuria / Q000235:genetics; D017674:Hypophosphatemia / Q000235:genetics*; D008297:Male; D009154:Mutation; D009397:Nephrocalcinosis / Q000235:genetics*; D010281:Parathyroid Hormone / Q000097:blood; D010375:Pedigree; D010641:Phenotype; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000235:genetics*
chemical_list: D010281:Parathyroid Hormone; C493554:SLC34A1 protein, human; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa