title: Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1.
abstract: Chondrodysplasia Grebe type (CGT) is an autosomal recessive disorder characterized by severe limb shortening and dysmorphogenesis. We have identified a causative point mutation in the gene encoding the bone morphogenetic protein (BMP)-like molecule, cartilage-derived morphogenetic protein-1 (CDMP-1). The mutation substitutes a tyrosine for the first of seven highly conserved cysteine residues in the mature active domain of the protein. We demonstrate that the mutation results in a protein that is not secreted and is inactive in vitro. It produces a dominant negative effect by preventing the secretion of other, related BMP family members. We present evidence that this may occur through the formation of heterodimers. The mutation and its proposed mechanism of action provide the first human genetic indication that composite expression patterns of different BMPs dictate limb and digit morphogenesis.
authors.affiliation: Craniofacial and Skeletal Diseases Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892, USA. tthomas@yoda.nidr.nih.gov
authors.forename: J T
authors.initials: JT
authors.lastname: Thomas
authors.forename: M W
authors.initials: MW
authors.lastname: Kilpatrick
authors.forename: K
authors.initials: K
authors.lastname: Lin
authors.forename: L
authors.initials: L
authors.lastname: Erlacher
authors.forename: P
authors.initials: P
authors.lastname: Lembessis
authors.forename: T
authors.initials: T
authors.lastname: Costa
authors.forename: P
authors.initials: P
authors.lastname: Tsipouras
authors.forename: F P
authors.initials: FP
authors.lastname: Luyten
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019485:Bone Morphogenetic Proteins; D019556:COS Cells; D017124:Conserved Sequence; D003545:Cysteine; D004392:Dwarfism / Q000235:genetics; D005260:Female; D005385:Fingers / Q000002:abnormalities; D005799:Genes, Dominant; D005808:Genes, Recessive; D055428:Growth Differentiation Factor 5; D006133:Growth Substances / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D006228:Hand Deformities, Congenital / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D009024:Morphogenesis; D010009:Osteochondrodysplasias / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D014162:Transfection; D014443:Tyrosine
chemical_list: D019485:Bone Morphogenetic Proteins; D055428:Growth Differentiation Factor 5; D006133:Growth Substances; D011994:Recombinant Proteins; D014443:Tyrosine; D003545:Cysteine