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

ID: 334903.0, MPI für molekulare Genetik / Research Group Development and Disease
A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
Authors:Lehmann, K.; Seemann, Petra; Silan, F.; Goecke, T. O.; Irgang, Markus; Kjaer, K. W.; Kjaergaard, S.; Mahoney, M. J.; Morlot, S.; Reissner, C.; Kerr, B.; Wilkie, A. O. M.; Mundlos, Stefan
Research Context:Report
Date of Publication (YYYY-MM-DD):2007-08-01
Title of Journal:The American Journal of Human Genetics : AJHG
Journal Abbrev.:Am. J. Hum. Genet.
Issue / Number:12
Start Page:388
End Page:396
Copyright:© 2007 The American Society of Human Genetics. All rights reserved.
Review Status:not specified
Audience:Experts Only
Abstract / Description:Brachydactyly type B (BDB) is characterized by terminal deficiency of fingers and toes, which is caused by heterozygous truncating mutations in the receptor tyrosine kinase–like orphan receptor 2 (ROR2) in the majority of patients. In a subset of ROR2-negative patients with BDB, clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis, we identified six different point mutations (P35A, P35S, A36P, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG). In contrast to previously described loss-of-function mutations in NOG, which are known to cause a range of conditions associated with abnormal joint formation but without BDB, the newly identified BDB mutations do not indicate a major loss of function, as suggested by calculation of free-binding energy of the modeled NOG-GDF5 complex and functional analysis of the micromass culture system. Rather, they presumably alter NOG’s ability to bind to BMPs and growth-differentiation factors (GDFs) in a subtle way, thus disturbing the intricate balance of BMP signaling. The combined features observed in this phenotypic subtype of BDB argue for a functional connection between BMP and ROR2 signaling and support previous findings of a modulating effect of ROR2 on the BMP-receptor pathway through the formation of a heteromeric complex of the receptors at the cell surface.
Comment of the Author/Creator:Address for correspondence and reprints: Dr. K. Lehmann, Institut für Medizinische Genetik, Universitätsmedizin Berlin Charité, Augustenburger Platz 1, 13353 Berlin, Germany
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Institut für Medizinische Genetik, Universitätsmedizin Berlin Charité, Berlin, Germany;
2.Department of Medical Genetics, Duzce School of Medicine, Duzce University, Duzce, Turkey;
3.Institut für Humangenetik und Anthropologie, Heinrich-Heine-Universität, Düsseldorf, Germany;
4.Wilhelm Johannsen Centre for Functional Genome Research, Institute of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen;
5.Department of Medical Genetics, John F. Kennedy Institute, Glostrup, Denmark;
6.Department of Genetics, Yale University School of Medicine, New Haven, CT;
7.Praxis für Humangenetik, Ärztliche Partnerschaft Wagner-Stibbe Hannover, Hannover, Germany;
8.Institut für Biologie, Molekulare Neurobiologie, Otto-von-Guericke-Universität, Magdeburg, Germany;
9.Regional Genetic Service, Royal Manchester Children’s Hospital, Manchester United Kingdom;
10.Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
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