Transforming Growth Factor-β1 Mutations in Camurati-Engelmann Disease Lead to Increased Signaling by Altering either Activation or Secretion of the Mutant Protein

Janssens, Katrien; Dijke, Peter ten; Ralston, Stuart H.; Bergmann, Carsten; Hul, Wim Van

doi:10.1074/jbc.m208857200

Cited by 109 publications

(92 citation statements)

References 38 publications

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“…It is intriguing that domain-specific germline mutations of TGFB1 cause Camurati-Engelmann disease (CED, OMIM #131300) (Kinoshita et al 2000) associated with marfanoid habitus, despite the absence of connective tissue fragility. TGFB1 mutations in CED were shown to cause increased TGFb signaling (Janssens et al 2003). These findings suggest that abnormal TGFb signaling could be responsible for the skeletal features of MFS.…”

Section: Germline Tgfbr Mutations and Connective Tissue Disordersmentioning

confidence: 79%

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

2006

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Marfan syndrome (MFS, OMIM #154700) is a hereditary connective tissue disorder, clinically presenting with cardinal features of skeletal, ocular, and cardiovascular systems. In classical MFS, changes in connective tissue integrity can be explained by defects in fibrillin-1, a major component of extracellular microfibrils. However, some of the clinical manifestations of MFS cannot be explained by mechanical properties alone. Recent studies manipulating mouse Fbn1 have provided new insights into the molecular pathogenesis of MFS. Dysregulation of transforming growth factor beta (TGFb) signaling in lung, mitral valve and aortic tissues has been implicated in mouse models of MFS. TGFBR2 and TGFBR1 mutations were identified in a subset of patients with MFS (MFS2, OMIM #154705) and other MFS-related disorders, including LoeysDietz syndrome (LDS, #OMIM 609192) and familial thoracic aortic aneurysms and dissections (TAAD2, #OMIM 608987). These data indicate that genetic heterogeneity exists in MFS and its related conditions and that regulation of TGFb signaling plays a significant role in these disorders.

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Section: Germline Tgfbr Mutations and Connective Tissue Disordersmentioning

confidence: 79%

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

2006

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“…These molecules can also form a larger covalent complex with a latent TGF-␤-binding protein (LTBP). Activation of TGF␤1, which occurs outside the cell, can occur as the result of low pH or proteolytic activity and results in the release of the active TGF␤1 dimer from the LAP and other inhibitory molecules so that it can now directly interact with the TGF␤1 receptors (Janssens et al 2003). Functional studies have shown that CED-causing mutations all act to increase SMAD-dependent TGF␤1 signaling, but by different mechanisms.…”

Section: Genetics Of Osteoporosis Genes and Development 2497mentioning

confidence: 99%

Genetic regulation of bone mass and susceptibility to osteoporosis

Ralston¹,

Crombrugghe²

2006

Genes Dev.

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293

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Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that the heritability of bone mineral density (BMD) and other determinants of fracture risksuch as ultrasound properties of bone, skeletal geometry, and bone turnover-is high, although heritability of fracture is modest. Many different genetic variants of modest effect size are likely to contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Linkage studies in rare Mendelian bone diseases have identified several previously unknown genes that play key roles in regulating bone mass and bone turnover. In many instances, subtle polymorphisms in these genes have also been found to regulate BMD in the general population. Although there has been extensive progress in identifying the genetic variants that regulate susceptibility to osteoporosis, most of the genes and genetic variants that regulate bone mass and susceptibility to osteoporosis remain to be discovered.Osteoporosis is characterized by reduced bone mass, alterations in the microarchitecture of bone tissue, reduced bone strength, and an increased risk of fracture (Kanis et al. 1994). Osteoporosis is a common condition that affects up to 30% of women and 12% of men at some point in life. The prevalence of osteoporosis increases with age due to an imbalance in the rate at which bone is removed and replaced during the bone remodeling cycle, which is an important physiological process that is essential for maintenance of a healthy skeleton. Many factors influence the risk of osteoporosis-including diet, physical activity, medication use, and coexisting diseases-but one of the most important clinical risk factors is a positive family history, emphasizing the importance of genetics in the pathogenesis of osteoporosis. In this article, we first review the evidence for a genetic contribution to osteoporosis and related phenotypes, and discuss the mechanisms by which mutations and polymorphisms in genes that regulate susceptibility to osteoporosis affect major signaling pathways in bone. Genetic influences on osteoporosisGenetic factors have long been recognized as playing an important role in the pathogenesis of osteoporosis. Evidence from twin and family studies suggests that between 50% and 85% of the variance in peak bone mass is genetically determined, depending on skeletal site and the age of the subjects studied (Smith et al. 1973;Pocock et al. 1987;Krall and Dawson-Hughes 1993;Gueguen et al. 1995). Heritability studies have also shown evidence of significant genetic effects on other key determinants of osteoporotic fracture risk, including quantitative ultrasound properties of bone (Arden et al. 1996), femoral neck geometry (Arden et al. 1996), muscle strength (Arden and Spector 1997), bone turnover markers (Hunter et al. 2001), and body mass index (Kaprio et al. 1995). The role of genetic factors in the pathogenesis of bon...

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“…Calvarial and pelvic bone thickening are also common (Janssens et al 2006). CED is caused by TGFB1 missense mutations in the LAP region or signal peptide that destabilize the disulfide binding needed for homodimerization of latent TGF-b1, resulting in increased TGF-b signaling through either premature activation or intracellular retention of the protein and intracrine signal transmission Janssens et al 2003Janssens et al , 2006. Clinical manifestations do not include fibrosis or aneurysm, and no evidence for increased TGF-b signaling has been described in the aortic wall or other tissues, suggesting that these mutations have tissue-specific effects on TGF-b activity.…”

Section: Gain Of Bone Mass In Camurati -Engelmann Diseasementioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Transforming Growth Factor-β1 Mutations in Camurati-Engelmann Disease Lead to Increased Signaling by Altering either Activation or Secretion of the Mutant Protein

Cited by 109 publications

References 38 publications

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

Genetic regulation of bone mass and susceptibility to osteoporosis

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

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