Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene.
Human disorders of phosphate (Pi) handling and hypophosphatemic rickets have been shown to result from mutations in PHEX, FGF23, and DMP1, presenting as X-linked recessive, autosomal-dominant, and autosomal-recessive patterns, respectively. We present the identification of an inactivating mutation in the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene causing autosomal-recessive hypophosphatemic rickets (ARHR) with phosphaturia by positional cloning. ENPP1 generates inorganic pyrophosphate (PPi), an essential physiologic inhibitor of calcification, and previously described inactivating mutations in this gene were shown to cause aberrant ectopic calcification disorders, whereas no aberrant calcifications were present in our patients. Our surprising result suggests a different pathway involved in the generation of ARHR and possible additional functions for ENPP1.
Levy-Litan
Varda
V
Department of Developmental Genetics and Virology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
Hershkovitz
Eli
E
Avizov
Luba
L
Leventhal
Neta
N
Bercovich
Dani
D
Chalifa-Caspi
Vered
V
Manor
Esther
E
Buriakovsky
Sophia
S
Hadad
Yair
Y
Goding
James
J
Parvari
Ruti
R
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D017124:Conserved Sequence; D053098:Familial Hypophosphatemic Rickets / Q000201:enzymology* / Q000235:genetics*; D000089703:Fibroblast Growth Factor-23; D020868:Gene Silencing; D005808:Genes, Recessive / Q000235:genetics*; D040181:Genetic Diseases, X-Linked; D020022:Genetic Predisposition to Disease; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011755:Pyrophosphatases / Q000737:chemistry / Q000235:genetics*; D055815:Young Adult
C000717427:FGF23 protein, human; D000089703:Fibroblast Growth Factor-23; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases