Hereditary hypophosphatemic rickets with hypercalciuria is not caused by mutations in the Na/Pi cotransporter NPT2 gene.
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.
Jones
Andrew O
AO
Department of Biology, McGill University, Montreal, Canada.|McGill University Health Centre Research Institute, Montreal, Canada.
Tzenova
Jordana
J
Department of Biology, McGill University, Montreal, Canada.
Frappier
Danielle
D
McGill University Health Centre Research Institute, Montreal, Canada.
Crumley
M Joyce
MJ
McGill University Health Centre Research Institute, Montreal, Canada.
Roslin
Nicole M
NM
McGill University Health Centre Research Institute, Montreal, Canada.
Kos
Claudine H
CH
Department of Biology, McGill University, Montreal, Canada.
Tieder
Martin
M
Department of Nephrology, Assaf Harofeh Medical Center, Beer Yaakov, Israel.
Langman
Craig B
CB
Department of Pediatric Nephrology, Northwestern University, Chicago, Illinois.
Proesmans
Willem
W
Department of Pediatrics, University Ziekenhuis Gasthuisberg, Leuven, Belgium.
Carpenter
Thomas O
TO
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
Rice
Allan
A
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
Anderson
Donald
D
Department of Pediatric Endocrinology, John Hunter Children's Hospital, Newcastle, Australia.
Morgan
Kenneth
K
Department of Human Genetics, McGill University, Montreal, Canada.|Department of Medicine, McGill University, Montreal, Canada.|McGill University Health Centre Research Institute, Montreal, Canada.
Fujiwara
T Mary
TM
Department of Human Genetics, McGill University, Montreal, Canada.|Department of Medicine, McGill University, Montreal, Canada.|McGill University Health Centre Research Institute, Montreal, Canada.
Tenenhouse
Harriet S
HS
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.
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
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