Mutations in the Transmembrane Natriuretic Peptide Receptor NPR-B Impair Skeletal Growth and Cause Acromesomelic Dysplasia, Type Maroteaux

• Published in: American journal of human genetics 2004-07, Vol.75 (1), p.27-34
• Main Authors: Bartels, Cynthia F., Bükülmez, Hülya, Padayatti, Pius, Rhee, David K., van Ravenswaaij-Arts, Conny, Pauli, Richard M., Mundlos, Stefan, Chitayat, David, Shih, Ling-Yu, Al-Gazali, Lihadh I., Kant, Sarina, Cole, Trevor, Morton, Jenny, Cormier-Daire, Valérie, Faivre, Laurence, Lees, Melissa, Kirk, Jeremy, Mortier, Geert R., Leroy, Jules, Zabel, Bernhard, Kim, Chong Ae, Crow, Yanick, Braverman, Nancy E., van den Akker, Focco, Warman, Matthew L.
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple; Adult; Biological and medical sciences; Bone and Bones - abnormalities; Bone and Bones - pathology; Bone Diseases, Developmental - genetics; Case-Control Studies; Cell Membrane - physiology; Dwarfism; Female; General aspects. Genetic counseling; Guanylate Cyclase - genetics; Humans; Male; Medical genetics; Medical sciences; Mutation - genetics; Protein Binding; Protein Folding; Receptors, Atrial Natriuretic Factor - genetics
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/422013

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.