title: Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux.
abstract: The homodimeric transmembrane receptor natriuretic peptide receptor B (NPR-B [also known as guanylate cyclase B, GC-B, and GUC2B]; gene name NPR2) produces cytoplasmic cyclic GMP from GTP on binding its extracellular ligand, C-type natriuretic peptide (CNP). CNP has previously been implicated in the regulation of skeletal growth in transgenic and knockout mice. The autosomal recessive skeletal dysplasia known as "acromesomelic dysplasia, type Maroteaux" (AMDM) maps to an interval that contains NPR2. We sequenced DNA from 21 families affected by AMDM and found 4 nonsense mutations, 4 frameshift mutations, 2 splice-site mutations, and 11 missense mutations. Molecular modeling was used to examine the putative protein change brought about by each missense mutation. Three missense mutations were tested in a functional assay and were found to have markedly deficient guanylyl cyclase activity. We also found that obligate carriers of NPR2 mutations have heights that are below the mean for matched controls. We conclude that, although NPR-B is expressed in a number of tissues, its major role is in the regulation of skeletal growth.
authors.affiliation: Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Cynthia F
authors.initials: CF
authors.lastname: Bartels
authors.forename: Hulya
authors.initials: H
authors.lastname: Bükülmez
authors.forename: Pius
authors.initials: P
authors.lastname: Padayatti
authors.forename: David K
authors.initials: DK
authors.lastname: Rhee
authors.forename: Conny
authors.initials: C
authors.lastname: van Ravenswaaij-Arts
authors.forename: Richard M
authors.initials: RM
authors.lastname: Pauli
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Shih
authors.forename: Lihadh I
authors.initials: LI
authors.lastname: Al-Gazali
authors.forename: Sarina
authors.initials: S
authors.lastname: Kant
authors.forename: Trevor
authors.initials: T
authors.lastname: Cole
authors.forename: Jenny
authors.initials: J
authors.lastname: Morton
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: Melissa
authors.initials: M
authors.lastname: Lees
authors.forename: Jeremy
authors.initials: J
authors.lastname: Kirk
authors.forename: Geert R
authors.initials: GR
authors.lastname: Mortier
authors.forename: Jules
authors.initials: J
authors.lastname: Leroy
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.forename: Chong Ae
authors.initials: CA
authors.lastname: Kim
authors.forename: Yanick
authors.initials: Y
authors.lastname: Crow
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Braverman
authors.forename: Focco
authors.initials: F
authors.lastname: van den Akker
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Warman
mesh_terms: D000015:Abnormalities, Multiple; D000328:Adult; D001848:Bone Diseases, Developmental / Q000235:genetics*; D001842:Bone and Bones / Q000002:abnormalities / Q000473:pathology*; D016022:Case-Control Studies; D002462:Cell Membrane / Q000502:physiology*; D004392:Dwarfism; D005260:Female; D006162:Guanylate Cyclase / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding; D017510:Protein Folding; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics*; D000099242:Atrial Natriuretic Factor Receptor B
chemical_list: D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B