title: Intact kinase homology domain of natriuretic peptide receptor-B is essential for skeletal development.
abstract: BACKGROUND
  Natriuretic peptide receptor-B (NPR-B, GC-B in rodents; gene name NPR2) is a guanylyl cyclase-coupled receptor that mediates the effect of C-type natriuretic peptide. Homozygous mutations in human NPR-B cause acromesomelic dysplasia, type Maroteaux (OMIM 602875), an autosomal recessive skeletal dysplasia. NPR-B has an intracellular kinase homology domain (KHD), which has no kinase activity, and its functional significance in vivo is currently unknown.
  
  
  OBJECTIVE
  We examined the functional significance of a novel NPR-B KHD mutation in humans.
  
  
  METHODS
  A 28-yr-old Japanese male presented with marked short stature (118.5 cm, -9.3 sd). His limbs showed marked shortening in the middle and distal segments. His parents had relatively short stature with height z-scores of -2.75 and -0.98 (his father and mother, respectively). Direct sequencing of coding region of the NPR2 gene of the family was performed. The mutant receptor activity was investigated by saturation binding assay and cGMP measurement. Additionally, interaction between the mutant and wild type allele was investigated by the titration experiments.
  
  
  RESULTS
  We identified a novel missense mutation L658F in KHD of NPR-B in homozygous and heterozygous states in the patient and his parents, respectively. The mutation conferred normal binding affinity for C-type natriuretic peptide but no discernible ligand-induced cGMP production. Furthermore, L658F mutant impaired wild-type NPR-B-mediated cGMP production in a dose-dependent manner, suggesting that short stature found in L658F heterozygote can be caused by its dominant-negative effect.
  
  
  CONCLUSIONS
  This study provides the first evidence that intact KHD of NPR-B is essential for skeletal development.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, 160-8582 Tokyo, Japan.
authors.forename: Rumi
authors.initials: R
authors.lastname: Hachiya
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ohashi
authors.forename: Yasutomi
authors.initials: Y
authors.lastname: Kamei
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suganami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Norimasa
authors.initials: N
authors.lastname: Mitsui
authors.forename: Masaaki
authors.initials: M
authors.lastname: Saitoh
authors.forename: Masako
authors.initials: M
authors.lastname: Sakuragi
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001846:Bone Development / Q000235:genetics*; D001848:Bone Diseases, Developmental / Q000000981:diagnostic imaging / Q000235:genetics*; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D006162:Guanylate Cyclase / Q000737:chemistry* / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010770:Phosphotransferases / Q000737:chemistry / Q000235:genetics; D017434:Protein Structure, Tertiary; D011859:Radiography; D017461:Receptors, Atrial Natriuretic Factor / Q000737:chemistry* / Q000235:genetics*; D014162:Transfection; D000099242:Atrial Natriuretic Factor Receptor B
chemical_list: D006162:Guanylate Cyclase; D010770:Phosphotransferases; D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B