title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
abstract: We describe a three-generation family with tall stature, scoliosis and macrodactyly of the great toes and a heterozygous p.Val883Met mutation in Npr2, the gene that encodes the CNP receptor NPR2 (natriuretic peptide receptor 2). When expressed in HEK293A cells, the mutant Npr2 cDNA generated intracellular cGMP (cyclic guanosine monophosphate) in the absence of CNP ligand. In the presence of CNP, cGMP production was greater in cells that had been transfected with the mutant Npr2 cDNA compared to wild-type cDNA. Transgenic mice in which the mutant Npr2 was expressed in chondrocytes driven by the promoter and intronic enhancer of the Col11a2 gene exhibited an enhanced production of cGMP in cartilage, leading to a similar phenotype to that observed in the patients. In addition, blood cGMP concentrations were elevated in the patients. These results indicate that p.Val883Met is a constitutive active gain-of-function mutation and elevated levels of cGMP in growth plates lead to the elongation of long bones. Our findings reveal a critical role for NPR2 in skeletal growth in both humans and mice, and may provide a potential target for prevention and treatment of diseases caused by impaired production of cGMP.
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Miura
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Namba
authors.forename: Makoto
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Ohata
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Ishida
authors.forename: Taichi
authors.initials: T
authors.lastname: Kitaoka
authors.forename: Takuo
authors.initials: T
authors.lastname: Kubota
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Hirai
authors.forename: Chikahisa
authors.initials: C
authors.lastname: Higuchi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Tsumaki
authors.forename: Hideki
authors.initials: H
authors.lastname: Yoshikawa
authors.forename: Norio
authors.initials: N
authors.lastname: Sakai
authors.forename: Toshimi
authors.initials: T
authors.lastname: Michigami
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D000818:Animals; D019902:Chondrocytes / Q000201:enzymology / Q000473:pathology; D006152:Cyclic GMP; D018076:DNA, Complementary; D005385:Fingers / Q000002:abnormalities / Q000473:pathology; D015870:Gene Expression; D006130:Growth Disorders / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D017880:Limb Deformities, Congenital / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D000099242:Atrial Natriuretic Factor Receptor B
chemical_list: D006152:Cyclic GMP; D018076:DNA, Complementary; D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B