Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1

Thomas, Jack; Mw, Kilpatrick; Kang, Lin; Erlacher, L; Lembessis, Peter; Costa, Teresa; Tsipouras, Petros; Fp, Luyten

doi:10.1038/ng0997-58

Cited by 333 publications

(226 citation statements)

References 31 publications

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“…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).…”

Section: Naturally Occurring Mutations In Bmps and Bmp Receptorsmentioning

confidence: 99%

The BMP signaling and in vivo bone formation

Cao

Chen

2005

Gene

269

197

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Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor β(TGFβ) superfamily. The roles of BMPs in embryonic development and cellular functions in postnatal and adult animals have been extensively studied in recent years. Signal transduction studies have revealed that Smads 1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction. Studies from transgenic and knockout mice and from animals and humans with naturally occurring mutations in BMPs and their signaling molecules have shown that BMP signaling plays critical roles in bone and cartilage development and postnatal bone formation. BMP activities are regulated at different molecular levels. Tissue-specific knockout of a specific BMP ligand, a subtype of BMP receptors or a specific signaling molecule is required to further determine the specific role of a BMP ligand, receptor or signaling molecule in a particular tissue.

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Section: Naturally Occurring Mutations In Bmps and Bmp Receptorsmentioning

confidence: 99%

The BMP signaling and in vivo bone formation

Cao

Chen

2005

Gene

269

197

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“…Drosophila decapentaplegic (DPP) and SCREW (BMP4 and BMP7 orthologs) are both required for proper spatial localization of DPP and this is proposed to be due to preferential transport of DPP/SCREW heterodimers within the embryo (11). Furthermore, mice carrying a point mutation that prevents proteolytic activation of BMP5, or humans carrying a point mutation that prevents secretion of the BMP family member growth and differentiation factor 5 (GDF5), display skeletal abnormalities that are more severe than those observed in the respective null mutants, most likely due to dominant negative effects on related BMPs that form heterodimers with endogenous BMP5 or GDF5 (12,13).…”

Section: Significancementioning

confidence: 99%

The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo

Neugebauer¹,

Kwon

Kim³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Bone morphogenetic proteins 4 and 7 (BMP4 and BMP7) are morphogens that signal as either homodimers or heterodimers to regulate embryonic development and adult homeostasis. BMP4/7 heterodimers exhibit markedly higher signaling activity than either homodimer, but the mechanism underlying the enhanced activity is unknown. BMPs are synthesized as inactive precursors that dimerize and are then cleaved to generate both the bioactive ligand and prodomain fragments, which lack signaling activity. Our study reveals a previously unknown requirement for the BMP4 prodomain in promoting heterodimer activity. We show that BMP4 and BMP7 precursor proteins preferentially or exclusively form heterodimers when coexpressed in vivo. In addition, we show that the BMP4 prodomain is both necessary and sufficient for generation of stable heterodimeric ligands with enhanced activity and can enable homodimers to signal in a context in which they normally lack activity. Our results suggest that intrinsic properties of the BMP4 prodomain contribute to the relative bioactivities of homodimers versus heterodimers in vivo. These findings have clinical implications for the use of BMPs as regenerative agents for the treatment of bone injury and disease.B one morphogenetic proteins (BMPs) are members of the TGFβ superfamily that were originally isolated as boneinducing morphogens and were subsequently found to play central roles during embryogenesis and in adult homeostasis (1). BMPs are clinically important therapeutic agents that are used to reverse bone loss caused by trauma, disease, and tumor resection (2). Their use as regenerative agents is limited, however, by their short half-life and low specific activity when implanted in vivo. Understanding how BMP activity is regulated is important for the development of more effective therapeutic agents for the treatment of bone injury and disease.BMPs bind to and activate a receptor complex consisting of type I and type II transmembrane serine/threonine kinases. Following ligand binding, activated receptors propagate their signal by phosphorylating one of the SMADs that is specific for the BMP pathway (SMAD1, -5, or -8). The phosphorylated Smads then form heterooligomers with the common Smad, Smad4, and this complex translocates into the nucleus where it binds to BMP response elements and activates transcription of target genes (1).BMPs are classified into subfamilies based on sequence homology. They signal as either homodimers, or as heterodimers from different subfamilies. For example, class I BMPs, which consist of BMP2 and BMP4, can heterodimerize with class II BMPs, consisting of BMP5-8 (3). Heterodimers composed of distinct BMP family members show a higher specific activity than do homodimers of either subunit. Homodimers of BMP2, -4, or -7, for example, can all induce bone formation, but heterodimers of BMP2 plus BMP7, or BMP4 plus BMP7 are significantly more potent (5-to 20-fold) than any of the homodimers in osteogenic differentiation assays (4-6). BMP2/7 and BMP4/7 heterodimers also sho...

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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Acromesomelic chondrodysplasias (ACDs) are characterized by disproportionate shortening of the appendicular skeleton, predominantly affecting the middle (forearms and forelegs) and distal segments (hands and feet). Here, we present two consanguineous families with missense (c.157T4C, p.(C53R)) or nonsense (c.657G4A, p.(W219*)) mutations in BMPR1B. Homozygous affected individuals show clinical and radiographic findings consistent with ACD-type Grebe. Functional analysis of the missense mutation C53R revealed that the mutated receptor was partially located at the cell membrane. In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay. Further, overexpression of the C53R mutation in an in vitro chondrogenesis assay showed no effect on cell differentiation, indicating a loss of function. The nonsense mutation (c.657G4A, p.(W219*)) introduces a premature stop codon, which is predicted to be subject to nonsense-mediated mRNA decay, causing reduced protein translation of the mutant allele. A lossof-function effect of both mutations causing recessive ACD-type Grebe is further supported by the mild brachydactyly or even non-penetrance of these mutations observed in the heterozygous parents. In contrast, dominant-negative BMPR1B mutations described previously are associated with autosomal-dominant brachydactyly-type A2.

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Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1

Cited by 333 publications

References 31 publications

The BMP signaling and in vivo bone formation

The BMP signaling and in vivo bone formation

The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo

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

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