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

Carine Le Goff 1 Clementine Mahaut 2 Lauren W Wang Slimane Allali 3 Avinash Abhyankar 4 Sacha Jensen 5 Louise Zylberberg 6 Gwenaelle Collod-Beroud 7 Damien Bonnet 8 Yasemin Alanay 9 Angela F Brady Marie-Pierre Cordier 10 Koen Devriendt 11 David Geneviève 12 Pelin Özlem Simsek Kiper 9 Hiroshi Kitoh 13 Deborah Krakow 14 Sally Ann Lynch 15 Martine Le Merrer 1 André Mégarbané 16 Geert Mortier 17 Sylvie Odent 18 Michel Polak 19 Marianne Rohrbach 20 David Sillence 21 Irene Stolte-Dijkstra 22 Andrea Superti-Furga 23 David L Rimoin Vicken Topouchian 24 Sheila Unger 25 Bernhard Zabel 26 Christine Bole-Feysot 27 Patrick Nitschke 28 Penny Handford 5 Jean-Laurent Casanova 29 Catherine Boileau 30 Suneel S Apte Arnold Munnich 1 Valérie Cormier-Daire 1
Abstract : Geleophysic (GD) and acromicric dysplasia (AD) belong to the acromelic dysplasia group and are both characterized by severe short stature, short extremities, and stiff joints. Although AD has an unknown molecular basis, we have previously identified ADAMTSL2 mutations in a subset of GD patients. After exome sequencing in GD and AD cases, we selected fibrillin 1 (FBN1) as a candidate gene, even though mutations in this gene have been described in Marfan syndrome, which is characterized by tall stature and arachnodactyly. We identified 16 heterozygous FBN1 mutations that are all located in exons 41 and 42 and encode TGFb-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFb signaling were consistent features in GD and AD fibro-blasts. Importantly, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a disruption of this interaction as the underlying mechanism of GD and AD phenotypes. Although enhanced TGFb signaling caused by FBN1 mutations can trigger either Marfan syndrome or GD and AD, our findings support the fact that TB5 mutations in FBN1 are responsible for short stature phenotypes.
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American Journal of Human Genetics, Elsevier (Cell Press), 2011, 89 (1), pp.7 - 14. 〈10.1016/j.ajhg.2011.05.012〉
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Carine Le Goff, Clementine Mahaut, Lauren W Wang, Slimane Allali, Avinash Abhyankar, et al.. Mutations in the TGFβ Binding-Protein-Like Domain 5 of FBN1 Are Responsible for Acromicric and Geleophysic Dysplasias. American Journal of Human Genetics, Elsevier (Cell Press), 2011, 89 (1), pp.7 - 14. 〈10.1016/j.ajhg.2011.05.012〉. 〈hal-01670058〉

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