Abstract
The term “fibrillinopathies” gathers various diseases with a wide spectrum of clinical features and severity but all share mutations in the fibrillin genes. The first described fibrillinopathy, Marfan syndrome (MFS), is a multisystem disease with a unique combination of skeletal, thoracic aortic aneurysm (TAA) and ocular features. The numerous FBN1 mutations identified in MFS are located all along the gene, leading to the same pathogenic mechanism. The geleophysic/acromicric dysplasias (GD/AD), characterized by short stature, short extremities, and joint limitation are described as “the mirror image” of MFS. Previously, in GD/AD patients, we identified heterozygous FBN1 mutations all affecting TGFβ-binding protein-like domain 5 (TB5). ADAMTS10, ADAMTS17 and, ADAMTSL2 are also involved in the pathogenic mechanism of acromelic dysplasia. More recently, in TAA patients, we identified mutations in THSD4, encoding ADAMTSL6, a protein belonging to the ADAMTSL family suggesting that ADAMTSL proteins are also involved in the Marfanoid spectrum. Together with human genetic data and generated knockout mouse models targeting the involved genes, we provide herein an overview of the role of fibrillin-1 in opposite phenotypes. Finally, we will decipher the potential biological cooperation of ADAMTS-fibrillin-1 involved in these opposite phenotypes.
Highlights
Fibrillins are the major glycoprotein components of microfibrils in the extracellular matrix (Sakai et al, 1986)
Mutations in ADAMTS genes were identified in acromelic dysplasias and mutations in THSD4 in HTAA suggesting that the ADAMTS proteins may have a functional link with fibrillin-1
Molecular Basis Using whole-exome sequencing on a cohort of heritable thoracic aortic aneurysm (TAA) and marfanoid patients without a known molecular basis, we identified a total of five pathogenic heterozygous variants in the THSD4 gene that encodes the extracellular protein ADAMTSL6
Summary
Fibrillins are the major glycoprotein components of microfibrils in the extracellular matrix (Sakai et al, 1986). Mutations in the fibrillin genes have been identified in various diseases referred to as fibrillinopathies (Aubart et al, 2016). These diseases represent a wide spectrum of disorders including MFS, Marfanoid-progeroid-lipodystrophy syndrome (MFLS), Shprintzen-Goldberg syndrome, acromelic dysplasias such as Weill Marchesani syndrome, GD/AD, and a wide spectrum of severity, ranging from lifethreatening neonatal forms to almost no clinical features in adults. Our review aims to summarize the knowledge focusing on a genetic and biological link between fibrillin-1 and the ADAMTS. We will highlight cooperation between ADAMTS and fibrillin-1 in these human disorders (Table 1)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
