Mutations in the TGFβ Binding-Protein-Like Domain 5 of FBN1 Are Responsible for Acromicric and Geleophysic Dysplasias

Goff, Carine Le; Mahaut, Clémentine; Wang, Lauren W.; Allali, Slimane; Abhyankar, Avinash; Jensen, Sacha A.; Zylberberg, Louise; Collod‐Béroud, Gwenaëlle; Bonnet, Damien; Alanay, Yasemin; Brady, Angela; Cordier, Marie‐Pierre; Devriendt, Koenraad; Geneviève, David; Kiper, Pelin Özlem Şimşek; Kitoh, Hiroshi; Krakow, Deborah; Lynch, Sally Ann; Merrer, Martine Le; Mégarbané, André; Mortier, Geert; Odent, Sylvie; Polak, Michel; Rohrbach, Marianne; Sillence, David; Stolte‐Dijkstra, Irene; Superti‐Furga, Andrea; Rimoin, David L.; Topouchian, Vicken; Unger, Sheila; Zabel, Bernhard; Bôle‐Feysot, Christine; Nitschké, Patrick; Handford, Penny A.; Casanova, Jean‐Laurent; Boileau, Cathérine; Apte, Suneel S.; Münnich, Arnold; Cormier‐Daire, Valérie

doi:10.1016/j.ajhg.2011.05.012

Cited by 202 publications

(299 citation statements)

References 15 publications

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“…49 Mutations are found in 2 hot spots: exons 37 and 38, which encode a domain containing an Arg-Gly-Asp motif (important in mediating cell-matrix interactions via integrin binding), and exons 41 and 42, which encode LTBP-like domains. 49,50 Interestingly, in both conditions, an enhanced TGF-β signaling, similar to the one found in MFS, has been observed. How similar disturbance of TGF-β signaling can lead to quite opposite phenotypes (eg, shorter limbs in geleophysic dysplasia and long limbs in MFS) needs further investigation but clearly suggests tissue-and domain-specific functions of FBN1 with regard to its modulation of the TGF-β signaling.…”

Section: A Better Understanding Of Pathogenesis Has Engendered Contromentioning

confidence: 64%

Genetics of Thoracic Aortic Aneurysm

Gillis

Laer

Loeys

2013

Circulation Research

158

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Aortic aneurysm, including both abdominal aortic aneurysm and thoracic aortic aneurysm, is the cause of death of 1% to 2% of the Western population. This review focuses only on thoracic aortic aneurysms and dissections. During the past decade, the genetic contribution to the pathogenesis of thoracic aortic aneurysms and dissections has revealed perturbed extracellular matrix signaling cascade interactions and deficient intracellular components of the smooth muscle contractile apparatus as the key mechanisms. Based on the study of different Marfan mouse models and the discovery of several novel thoracic aortic aneurysm genes, the involvement of the transforming growth factor-β signaling pathway has opened unexpected new avenues. Overall, these discoveries have 3 important consequences. First, the pathogenesis of thoracic aortic aneurysms and dissections is better understood, although some controversy still exists. Second, the management strategies for the medical and surgical treatment of thoracic aortic aneurysms and dissections are becoming increasingly gene-tailored. Third, the pathogenetic insights have delivered new treatment options that are currently being investigated in large clinical trials.

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Section: A Better Understanding Of Pathogenesis Has Engendered Contromentioning

confidence: 64%

Genetics of Thoracic Aortic Aneurysm

Gillis

Laer

Loeys

2013

Circulation Research

158

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“…In line with this, specific missense mutations in exons 41 and 42 that encode the TGF-β-binding protein-like domain 5 associate with higher TGF-β levels in acromicric and geleophysic dysplasias compared with controls. 29 …”

Section: Discussionmentioning

confidence: 99%

Total Serum Transforming Growth Factor‐β1 Is Elevated in the Entire Spectrum of Genetic Aortic Syndromes

Hillebrand

Millot

Sheikhzadeh

et al. 2014

Clinical Cardiology

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Background: Total serum transforming growth factor-beta 1 (tsTGF-β1) is increased in patients with Marfan syndrome (MFS), but it has not been assessed in thoracic aortic aneurysm and dissection (TAAD), Loeys-Dietz syndrome (LDS), and bicuspid aortic valve disease (BAVD). Hypothesis: tsTGF-β1 is increased in genetic aortic syndromes including TAAD, LDS, MFS, and BAVD. Methods: We measured tsTGF-β1 and performed sequencing of the genes FBN1, TGFBR1, and TGFBR2 in 317 consecutive patients with suspected or known genetic aortic syndrome (167 men, 150 women; mean age 43 ± 14 years). TAAD was diagnosed in 20, LDS in 20, MFS in 128, and BAVD in 30 patients, and genetic aortic syndrome was excluded in 119 patients. Results: Elevated tsTGF-β1 levels were associated with causative gene mutations (P = 0.008), genetic aortic syndrome (P = 0.009), and sporadic occurrence of genetic aortic syndrome (P = 0.048), whereas only genetic aortic syndrome qualified as an independent predictor of tsTGF-β1 (P = 0.001). The tsTGF-β1 levels were elevated in FBN1 and NOTCH1 mutations vs patients without mutations (both P = 0.004), and in NOTCH1 mutations vs ACTA2/MYH11 mutations (P = 0.015). Similarly, tsTGF-β1 levels were elevated in MFS (P = 0.003) and in BAVD (P = 0.006) vs patients without genetic aortic syndrome. In contrast to specific clinical features of MFS, FBN1 in-frame mutations (P = 0.019) were associated with increased tsTGF-β1 levels. Conclusions: tsTGF-β1 is elevated in the entire spectrum of genetic aortic syndromes. However, gradual differences in the increases of tsTGF-β1 levels may mirror different degrees of alteration of tsTGF-β1 signaling in different genetic aortic syndromes.

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“…Clinical manifestations of the acromicric (AD; OMIM 102370) and GD (OMIM 231050) include short stature, joint defects and thickened skin (Ref. 160).…”

Section: Wms and Acromicric And Gdmentioning

confidence: 99%

Elastic fibres in health and disease

Baldwin

Simpson

Steer

et al. 2013

Expert Rev. Mol. Med.

240

158

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Elastic fibres are insoluble components of the extracellular matrix of dynamic connective tissues such as skin, arteries, lungs and ligaments. They are laid down during development, and comprise a cross-linked elastin core within a template of fibrillin-based microfibrils. Their function is to endow tissues with the property of elastic recoil, and they also regulate the bioavailability of transforming growth factor β. Severe heritable elastic fibre diseases are caused by mutations in elastic fibre components; for example, mutations in elastin cause supravalvular aortic stenosis and autosomal dominant cutis laxa, mutations in fibrillin-1 cause Marfan syndrome and Weill–Marchesani syndrome, and mutations in fibulins-4 and -5 cause autosomal recessive cutis laxa. Acquired elastic fibre defects include dermal elastosis, whereas inflammatory damage to fibres contributes to pathologies such as pulmonary emphysema and vascular disease. This review outlines the latest understanding of the composition and assembly of elastic fibres, and describes elastic fibre diseases and current therapeutic approaches.

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Mutations in the TGFβ Binding-Protein-Like Domain 5 of FBN1 Are Responsible for Acromicric and Geleophysic Dysplasias

Cited by 202 publications

References 15 publications

Genetics of Thoracic Aortic Aneurysm

Genetics of Thoracic Aortic Aneurysm

Total Serum Transforming Growth Factor‐β1 Is Elevated in the Entire Spectrum of Genetic Aortic Syndromes

Elastic fibres in health and disease

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