title: SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis.
abstract: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of autosomal recessive inheritance that was first described in a large consanguineous Bedouin kindred. HHRH is characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histological evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption. We performed a genomewide linkage scan combined with homozygosity mapping, using genomic DNA from a large consanguineous Bedouin kindred that included 10 patients who received the diagnosis of HHRH. The disease mapped to a 1.6-Mbp region on chromosome 9q34, which contains SLC34A3, the gene encoding the renal sodium-phosphate cotransporter NaP(i)-IIc. Nucleotide sequence analysis revealed a homozygous single-nucleotide deletion (c.228delC) in this candidate gene in all individuals affected by HHRH. This mutation is predicted to truncate the NaP(i)-IIc protein in the first membrane-spanning domain and thus likely results in a complete loss of function of this protein in individuals homozygous for c.228delC. In addition, compound heterozygous missense and deletion mutations were found in three additional unrelated HHRH kindreds, which supports the conclusion that this disease is caused by SLC34A3 mutations affecting both alleles. Individuals of the investigated kindreds who were heterozygous for a SLC34A3 mutation frequently showed hypercalciuria, often in association with mild hypophosphatemia and/or elevations in 1,25-dihydroxyvitamin D levels. We conclude that NaP(i)-IIc has a key role in the regulation of phosphate homeostasis.
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. cbergwitz@partners.org
authors.forename: Clemens
authors.initials: C
authors.lastname: Bergwitz
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Roslin
authors.forename: Martin
authors.initials: M
authors.lastname: Tieder
authors.forename: J C
authors.initials: JC
authors.lastname: Loredo-Osti
authors.forename: Murat
authors.initials: M
authors.lastname: Bastepe
authors.forename: Hilal
authors.initials: H
authors.lastname: Abu-Zahra
authors.forename: Danielle
authors.initials: D
authors.lastname: Frappier
authors.forename: Kelly
authors.initials: K
authors.lastname: Burkett
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Carpenter
authors.forename: Donald
authors.initials: D
authors.lastname: Anderson
authors.forename: Michele
authors.initials: M
authors.lastname: Garabedian
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sermet
authors.forename: T Mary
authors.initials: TM
authors.lastname: Fujiwara
authors.forename: Kenneth
authors.initials: K
authors.lastname: Morgan
authors.forename: Harriet S
authors.initials: HS
authors.lastname: Tenenhouse
authors.forename: Harald
authors.initials: H
authors.lastname: Juppner
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D018912:Arabs / Q000235:genetics; D002648:Child; D002874:Chromosome Mapping; D053098:Familial Hypophosphatemic Rickets / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D006579:Heterozygote; D006706:Homeostasis; D006801:Humans; D053565:Hypercalciuria / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010710:Phosphates / Q000378:metabolism*; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000235:genetics* / Q000502:physiology*
chemical_list: D010710:Phosphates; C493562:SLC34A3 protein, human; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc