title: Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria.
abstract: BACKGROUND
  Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder, characterized by hypophosphatemia and rickets/osteomalacia with increased serum 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] resulting in hypercalciuria.
  
  
  OBJECTIVE
  Our objective was to determine whether mutations in the SLC34A3 gene, which encodes sodium-phosphate cotransporter type IIc, are responsible for the occurrence of HHRH.
  
  
  METHODS
  Mutation analysis of exons and adjacent introns in the SLC34A3 gene was conducted at an academic research laboratory and medical center.
  
  
  METHODS
  Members of two unrelated families with HHRH participated in the study.
  
  
  RESULTS
  Two affected siblings in one family were homozygous for a 101-bp deletion in intron 9. Haplotype analysis of the SLC34A3 locus in the family showed that the two deletions are on different haplotypes. An unrelated individual with HHRH was a compound heterozygote for an 85-bp deletion in intron 10 and a G-to-A substitution at the last nucleotide in exon 7. The intron 9 deletion (and likely the other two mutations) identified in this study causes aberrant RNA splicing. Sequence analysis of the deleted regions revealed the presence of direct repeats of homologous sequences.
  
  
  CONCLUSIONS
  HHRH is caused by biallelic mutations in the SLC34A3 gene. Haplotype analysis suggests that the two intron 9 deletions arose independently. The identification of three independent deletions in introns 9 and 10 suggests that the SLC34A3 gene may be susceptible to unequal crossing over because of sequence misalignment during meiosis.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, 541 North Clinical Drive, Clinical Building 459, Indianapolis, IN 46202-5121, USA.
authors.forename: Shoji
authors.initials: S
authors.lastname: Ichikawa
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Sorenson
authors.forename: Erik A
authors.initials: EA
authors.lastname: Imel
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Friedman
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Gertner
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Econs
mesh_terms: D001483:Base Sequence; D002118:Calcium / Q000652:urine*; D002648:Child; D002675:Child, Preschool; D017353:Gene Deletion; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000235:genetics* / Q000652:urine; D007223:Infant; D007438:Introns; D007669:Kidney Calculi / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000235:genetics*
chemical_list: C493562:SLC34A3 protein, human; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc; D002118:Calcium