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

详细信息    查看全文

• 作者：Carine Le  ; Goff¹ ; Clé ; mentine Mahaut¹ ; Lauren  ; W. Wang² ; Slimane Allali¹ ; Avinash Abhyankar³ ; Sacha Jensen⁴ ; Louise Zylberberg⁵ ; Gwenaelle Collod-Beroud⁶ ; ⁷ ; Damien Bonnet⁸ ; Yasemin Alanay⁹ ; Angela  ; F. Brady¹⁰ ; Marie-Pierre Cordier¹¹ ; Koen Devriendt¹² ; David Genevieve¹³ ; Pelin  ; Ö ; zlem Simsek Kiper⁹ ; Hiroshi Kitoh¹⁴ ; Deborah Krakow¹⁵ ; Sally  ; Ann Lynch¹⁶ ; Martine Le  ; Merrer¹ ; André ; Mé ; garbane¹⁷ ; Geert Mortier¹⁸ ; Sylvie Odent¹⁹ ; Michel Polak²⁰ ; Marianne Rohrbach²¹ ; David Sillence²² ; Irene Stolte-Dijkstra²³ ; Andrea Superti-Furga²⁴ ; David  ; L. Rimoin²⁵ ; Vicken Topouchian²⁶ ; Sheila Unger²⁴ ; Bernhard Zabel²⁷ ; Christine Bole-Feysot²⁸ ; Patrick Nitschke²⁹ ; Penny Handford⁴ ; Jean-Laurent Casanova³ ; ³⁰ ; Catherine Boileau³¹ ; Suneel  ; S. Apte² ; Arnold Munnich¹ ; Valé ; rie Cormier-Daire¹ ; ^{valerie.cormier-daire@inserm.fr"" rel=""nofollow}
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：15 July 2011
• 年：2011
• 卷：89
• 期：1
• 页码：7-14
• 全文大小：783 K

文摘

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.