2. Academic Validation
  3. Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias

Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias

  • Am J Hum Genet. 2011 Jul 15;89(1):7-14. doi: 10.1016/j.ajhg.2011.05.012.
Carine Le Goff 1,  Clémentine Mahaut,  Lauren W Wang,  Slimane Allali,  Avinash Abhyankar,  Sacha Jensen,  Louise Zylberberg,  Gwenaelle Collod-Beroud,  Damien Bonnet,  Yasemin Alanay,  Angela F Brady,  Marie-Pierre Cordier,  Koen Devriendt,  David Genevieve,  Pelin Özlem Simsek Kiper,  Hiroshi Kitoh,  Deborah Krakow,  Sally Ann Lynch,  Martine Le Merrer,  André Mégarbane,  Geert Mortier,  Sylvie Odent,  Michel Polak,  Marianne Rohrbach,  David Sillence,  Irene Stolte-Dijkstra,  Andrea Superti-Furga,  David L Rimoin,  Vicken Topouchian,  Sheila Unger,  Bernhard Zabel,  Christine Bole-Feysot,  Patrick Nitschke,  Penny Handford,  Jean-Laurent Casanova,  Catherine Boileau,  Suneel S Apte,  Arnold Munnich,  Valérie Cormier-Daire
Affiliations

Affiliation

  • 1 Department of Genetics, Université Paris Descartes, Unité Institut National de la Santé et de la Recherche Médicale, Hôpital Necker Enfants Malades, Paris, France.
PMID: 21683322 DOI: 10.1016/j.ajhg.2011.05.012
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 TGFβ-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFβ signaling were consistent features in GD and AD fibroblasts. 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 TGFβ 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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