Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3.
Hypophosphatemia due to isolated renal phosphate wasting results from a heterogeneous group of disorders. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive form that is characterized by reduced renal phosphate reabsorption, hypophosphatemia, and rickets. It can be distinguished from other forms of hypophosphatemia by increased serum levels of 1,25-dihydroxyvitamin D resulting in hypercalciuria. Using SNP array genotyping, we mapped the disease locus in two consanguineous families to the end of the long arm of chromosome 9. The candidate region contained a sodium-phosphate cotransporter gene, SLC34A3, which has been shown to be expressed in proximal tubulus cells. Sequencing of this gene revealed disease-associated mutations in five families, including two frameshift and one splice-site mutation. Loss of function of the SLC34A3 protein presumably results in a primary renal tubular defect and is compatible with the HHRH phenotype. We also show that the phosphaturic factor FGF23 (fibroblast growth factor 23), which is increased in X-linked hypophosphatemic rickets and carries activating mutations in autosomal dominant hypophosphatemic rickets, is at normal or low-normal serum levels in the patients with HHRH, further supporting a primary renal defect. Identification of the gene mutated in a further form of hypophosphatemia adds to the understanding of phosphate homeostasis and may help to elucidate the interaction of the proteins involved in this pathway.
Lorenz-Depiereux
Bettina
B
Institute of Human Genetics, GSF National Research Center for Environment and Health, Munich-Neuherberg, Germany.
Benet-Pages
Anna
A
Eckstein
Gertrud
G
Tenenbaum-Rakover
Yardena
Y
Wagenstaller
Janine
J
Tiosano
Dov
D
Gershoni-Baruch
Ruth
R
Albers
Norbert
N
Lichtner
Peter
P
Schnabel
Dirk
D
Hochberg
Ze'ev
Z
Strom
Tim M
TM
D000818:Animals; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D004252:DNA Mutational Analysis; D053098:Familial Hypophosphatemic Rickets / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D040181:Genetic Diseases, X-Linked; D008040:Genetic Linkage; D006801:Humans; D053565:Hypercalciuria / Q000235:genetics*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000235:genetics*
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; C493562:SLC34A3 protein, human; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23