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

Carine Le Goff, Clementine 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 Ozlem Simsek Kiper, Hiroshi Kitoh, Deborah Krakow, Sally Ann Lynch, Martine Le Merrer, Andre MegarbaneGeert 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, Valerie Cormier-Dairel*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    172 Citations (Scopus)


    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 All 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 TGF beta-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGF beta signaling were consistent features in GD and AD fibroblasts. Importantly, a direct interaction between ADAMTS12 and FBN1 was demonstrated, suggesting a disruption of this interaction as the underlying mechanism of GD and AD phenotypes. Although enhanced TGF beta 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.

    Original languageEnglish
    Pages (from-to)7-14
    Number of pages8
    JournalAmerican Journal of Human Genetics
    Issue number1
    Publication statusPublished - 15-Jul-2011


    • GENE
    • MATRIX

    Cite this