A human chondrodysplasia due to a mutation in a TGF-β superfamily member

Abstract

The TGF-beta superfamily comprises a number of functionally diverse growth factors/signalling molecules (1) which elicit their response upon binding to serine-threonine kinase receptors (2). We recently reported the isolation and characterization of two new members of the family, designated cartilage-derived morphogenetic protein (CDMP) 1 and 2 (ref. 3) which are closely related to the sub-family of bone morphogenetic proteins. CDMP-1 is predominantly expressed at sites of skeletal morphogenesis (3), and we now show that a mutation in hCDMP-1 is associated with a recessive human chondrodysplasia (acromesomelic chondrodysplasia, Hunter-Thompson type (4,5)). The disorder, characterized by skeletal abnormalities restricted to the limbs andlimb joints, is phenotypically similar to murine brachypodism (bp) which is due to mutations in growth/differentiation factor-5 (Gdf-5) (6), the mouse homologue of hCDMP-1. Affected individuals are homozygous for a 22-bp (tandem-duplication) frameshift mutation in the mature region of CDMP-1. The resulting phenotype provides direct evidence for the involvement of CDMP-1 in human skeletal development and represents the first human disorder attributable to a mutation in a TGF-beta superfamily member.

Mechanisms of digit formation: Human malformation syndromes tell the story

“…Mutations in the prodomain of GDF5 cause a recessive form of BDC, presumably by means of a gene dosage effect . GDF5 is pivotal for chondrogenesis in humans, because homozygous loss of function mutations in GDF5 cause recessive generalized acromesomelic chondrodysplasia of the Grebe (MIM#200700), Hunter-Thomson (MIM#201250), and Du Pan (MIM#228900) type (Thomas et al, 1996Faiyaz-Ul-Haque et al, 2002). Furthermore, recessive homozygous mutations in the high affinity receptor BMPR1B also cause a severe form of acromesomelic chondrodysplasia with brachydactyly (Demirhan et al, 2005).…”

The BMP signaling and in vivo bone formation

“…Mutations in the Bmp5 gene are associated with a wide range of skeletal defects, including reductions in long bone width and the size of several vertebral processes and an overall lower body mass (Kingsley et al, 1992;Mikic et al, 1995). Mutations in growth/ differentiation factor-5 (Gdf5 and CDMP-1) gene result in brachypodism in mice (Storm et al, 1994) and chondrodysplasia in humans (Thomas et al, 1996(Thomas et al, , 1997. Both Bmp5 and Gdf5 genes are localized on chromosome 2 in mice and on chromosome 20 in humans (Storm et al, 1994).…”

Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe

“…3 All reported mutations in GDF5 associated with ACD are caused by a homozygous functional loss of GDF5, which is caused by either deletions, duplications, or insertions leading to a premature translational stop or caused by point mutations targeting the cleavage site or the mature domain of GDF5, thereby compromising its regular function. [4][5][6][7][8][9][10][11][12][13] Interestingly, one individual with a homozygous mutation in BMPR1B has been reported presenting with a subtype of ACD with additional genital anomalies, 14 implicating that mutations in the ligand and its receptor can cause similar phenotypes. Heterozygous carriers of dominant-negative mutations in BMPR1B are usually affected by brachydactyly-type A2 (BDA2; MIM number 112600), which is characterized by a shortened middle phalanx of the index finger and variable clinodactyly of the fifth finger.…”