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

Carine Le Goff (1) , Clementine C. Mahaut (1) , Lauren W Wang , Slimane Allali (2) , Avinash Abhyankar (3) , Sacha Jensen (4) , Louise Zylberberg (5) , Gwenaelle Collod-Beroud (6) , Damien Bonnet (7) , Yasemin Alanay (8) , Angela F Brady , Marie-Pierre Cordier (9) , Koen Devriendt (10) , David Geneviève (11) , Pelin Özlem Simsek Kiper (8) , Hiroshi Kitoh (12) , Deborah Krakow (13) , Sally Ann Lynch (14) , Martine Le Merrer (1) , André Mégarbané (15) , Geert Mortier (16) , Sylvie Odent (17) , Michel Polak (18) , Marianne Rohrbach (19) , David Sillence (20) , Irene Stolte-Dijkstra (21) , Andrea Superti-Furga (22) , David L Rimoin , Vicken Topouchian (23) , Sheila Unger (24) , Bernhard Zabel (25) , Christine Bole-Feysot (26) , Patrick Nitschke (27) , Penny A. Handford (4) , Jean-Laurent Casanova (28) , Catherine Boileau (29) , Suneel S Apte , Arnold Munnich (1) , Valérie Cormier-Daire (1)

1 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
2 Hôpital Bicêtre
3 St. Giles Laboratory of Human Genetics of Infectious Diseases
4 Department of Biochemistry [Oxford]
5 IBCP - Institut de biologie et chimie des protéines [Lyon]
6 LGMR - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques
7 Service de cardiologie pédiatrique [CHU Necker]
8 Department of Pediatrics
9 Service de cytogénétique constitutionnelle
10 Institute of Child Health
11 Service de génétique médicale [Montpellier]
12 Department of Orthopaedic Surgery
13 Department of Molecular Cellular and Developmental Biology
14 Our Lady's hospital for Sick Children
15 Unité de génétique médicale
16 Department of Medical Genetics
17 Unité de génétique médicale
18 GMM - Génétique des maladies multifactorielles
19 Clinical Genetics
20 Academic Department of Medical Genetics
21 Department of Clinical Genetics
22 Service de Pédiatrie
23 Service de chirurgie orthopédique pédiatrique
24 Service de Génétique humaine
25 Centre for Pediatrics and Adolescent Medicine
26 Endocrinologie moléculaire
27 BIP-D - Plate Forme Paris Descartes de Bioinformatique
28 Inserm U980 - Génétique Humaine des Maladies Infectieuses
29 Service de cardiologie

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.

Domaines: Biologie moléculaire; Génétique humaine

Carine Le Goff, Clementine C. 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, 2011, 89 (1), pp.7 - 14. ⟨10.1016/j.ajhg.2011.05.012⟩. ⟨hal-01670058⟩