title: Hereditary hypophosphatemic rickets with hypercalciuria is not caused by mutations in the Na/Pi cotransporter NPT2 gene.
abstract: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a renal phosphate (Pi) wasting disease first described in an extended Bedouin kindred, is characterized by hypophosphatemia, elevated serum 1,25-dihydroxyvitamin D levels, hypercalciuria, rickets, and osteomalacia. Correction of all abnormalities, except for renal Pi wasting, can be achieved by oral Pi supplementation. These findings and the demonstration that mice that are homozygous for the disrupted Na/Pi cotransporter gene Npt2 exhibit many of the biochemical features of HHRH suggested that mutations in the human orthologue NPT2 might be responsible for HHRH. The NPT2 gene in affected individuals from the Bedouin kindred and four small families was screened for mutations to test this hypothesis. No putative disease-causing mutation was found. Two single nucleotide polymorphisms (SNP), a silent substitution in exon 7 and a nucleotide substitution in intron 4, were identified, and neither consistently segregated with HHRH in the Bedouin kindred. Linkage analysis indicated that the two NPT2 intragenic SNP as well as five microsatellite markers in the NPT2 gene region were not linked to HHRH in the Bedouin kindred. Therefore, this is evidence to exclude NPT2 as a candidate gene for HHRH in the families that were studied.
authors.affiliation: Department of Biology, McGill University, Montreal, Canada.|McGill University Health Centre Research Institute, Montreal, Canada.
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Jones
authors.affiliation: Department of Biology, McGill University, Montreal, Canada.
authors.forename: Jordana
authors.initials: J
authors.lastname: Tzenova
authors.affiliation: McGill University Health Centre Research Institute, Montreal, Canada.
authors.forename: Danielle
authors.initials: D
authors.lastname: Frappier
authors.affiliation: McGill University Health Centre Research Institute, Montreal, Canada.
authors.forename: M Joyce
authors.initials: MJ
authors.lastname: Crumley
authors.affiliation: McGill University Health Centre Research Institute, Montreal, Canada.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Roslin
authors.affiliation: Department of Biology, McGill University, Montreal, Canada.
authors.forename: Claudine H
authors.initials: CH
authors.lastname: Kos
authors.affiliation: Department of Nephrology, Assaf Harofeh Medical Center, Beer Yaakov, Israel.
authors.forename: Martin
authors.initials: M
authors.lastname: Tieder
authors.affiliation: Department of Pediatric Nephrology, Northwestern University, Chicago, Illinois.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Langman
authors.affiliation: Department of Pediatrics, University Ziekenhuis Gasthuisberg, Leuven, Belgium.
authors.forename: Willem
authors.initials: W
authors.lastname: Proesmans
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Carpenter
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Allan
authors.initials: A
authors.lastname: Rice
authors.affiliation: Department of Pediatric Endocrinology, John Hunter Children's Hospital, Newcastle, Australia.
authors.forename: Donald
authors.initials: D
authors.lastname: Anderson
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Canada.|Department of Medicine, McGill University, Montreal, Canada.|McGill University Health Centre Research Institute, Montreal, Canada.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Morgan
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Canada.|Department of Medicine, McGill University, Montreal, Canada.|McGill University Health Centre Research Institute, Montreal, Canada.
authors.forename: T Mary
authors.initials: TM
authors.lastname: Fujiwara
authors.affiliation: Department of Biology, McGill University, Montreal, Canada.|Department of Human Genetics, McGill University, Montreal, Canada.|Department of Pediatrics, McGill University, Montreal, Canada.|McGill University Health Centre Research Institute, Montreal, Canada.
authors.forename: Harriet S
authors.initials: HS
authors.lastname: Tenenhouse
mesh_terms: D001483:Base Sequence; D002118:Calcium / Q000652:urine; D002352:Carrier Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D010710:Phosphates / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D027981:Symporters
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D010710:Phosphates; C493548:SLC17A2 protein, human; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D027981:Symporters; D012964:Sodium; D002118:Calcium