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          Institute: MPI für molekulare Genetik     Collection: Research Group Development and Disease     Display Documents

ID: 228710.0, MPI für molekulare Genetik / Research Group Development and Disease
Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux
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.
Date of Publication (YYYY-MM-DD):2004-07
Title of Journal:American Journal of Human Genetics
Journal Abbrev.:Am J Hum Genet
Issue / Number:1
Start Page:27
End Page:34
Copyright:© 2004 by The American Society of Human Genetics
Review Status:not specified
Audience:Experts Only
Abstract / Description: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.
Comment of the Author/Creator:Published online: 2004-05-14
External Publication Status:published
Document Type:Article
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:Departments of Genetics, Epidemiology and Biostatistics, Biochemistry, and Pediatrics, Case Western Reserve University School of Medicine, Center for Human Genetics, University Hospitals of Cleveland, and Department of Pediatrics, Metro Health Medical Center, Cleveland; Department of Human Genetics, University Medical Centre Nijmegen, Nijmegen, The Netherlands;
Departments of Pediatrics and Medical Genetics, University of Wisconsin–Madison, Madison, WI;
Institut für Medizinische Genetik Charité, Campus Virchow, Berlin;
Medical Genetics, Hospital for Sick Children, Toronto; Center for Human and Molecular Genetics, University of Medicine and Dentistry of New Jersey, Newark, NJ;
Department of Pediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates;
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands;
Clinical Genetics Unit, Birmingham Women's Healthcare, and Department of Pediatric Endocrinology, Birmingham Children's Hospital, Birmingham, United Kingdom;
Department of Medical Genetics, Hopital Necker, Paris;
Genetics Center, Hopital d'Enfants, Dijon, France; Department of Clinical Genetics, Great Ormond Street Hospital, London;
Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium;
Children's Hospital, University of Mainz, Mainz, Germany; Department of Genetics, University of São Paulo, São Paulo, Brazil;
Department of Clinical Genetics, The Leeds Teaching Hospital, Leeds, United Kingdom;
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore
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