Brachydactyly type C caused by a homozygous missense mutation in the prodomain of CDMP1

• Published in: American journal of medical genetics. Part A Vol. 124A; no. 4; pp. 356 - 363
• Main Authors: Schwabe, Georg C., Türkmen, Seval, Leschik, Gundula, Palanduz, Sukru, Stöver, Brigitte, Goecke, Timm O., Mundlos, Stefan
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.02.2004
• Subjects: Adolescent; Amino Acid Motifs; Amino Acid Sequence; Base Sequence; Bone Morphogenetic Proteins - chemistry; Bone Morphogenetic Proteins - genetics; brachydactyly; CDMP1; Child; Female; Gdf5; Growth Differentiation Factor 5; Hand Deformities, Congenital - genetics; Homozygote; Humans; Male; MCPP; Molecular Sequence Data; Mutation, Missense; Pedigree; prodomain; Protein Precursors - genetics; Protein Structure, Tertiary; TGF-β; Turkey; Turkey
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.20349

Brachydactyly type C (BDC) is characterized by shortening of the middle phalanges of the index, middle, and little finger with hyperphalangy, usually of the index and middle finger. Heterozygous mutations of the cartilage derived morphogenetic protein‐1 (CDMP1) resulting in a loss of function have been reported in BDC. We here describe a large kindred with a semi‐dominant form of BDC and pronounced ulnar deviation of the second and third digits. In this family a novel homozygous missense mutation was identified (517A > G) changing methionine to valine at amino acid position 173. The mutation is located within a highly conserved seven amino acid region of the prodomain of CDMP1. Hand radiographs of heterozygous mutation carriers showed mild shortening of the metacarpals IV and V; a finding confirmed by the analysis of their metacarpophalangeal profiles (MCPPs). The mutation described here points toward an important function of the prodomain for the folding, secretion, and availability of biologically active CDMP1. © 2003 Wiley‐Liss, Inc.