Pathogenic variants affecting the TB5 domain of the fibrillin-1 protein: not only in geleophysic/acromicric dysplasias but also in Marfan syndrome.

BACKGROUND: Marfan syndrome (MFS) is a multisystem disease with a unique combination of skeletal, cardiovascular and ocular features. Geleophysic/acromicric dysplasias (GPHYSD/ACMICD), characterised by short stature and extremities, are described as 'the mirror image' of MFS. The numerous FBN1 pathogenic variants identified in MFS are located all along the gene and lead to the same final pathogenic sequence. Conversely, in GPHYSD/ACMICD, the 28 known heterozygous FBN1 pathogenic variants all affect exons 41-42 encoding TGFß-binding protein-like domain 5 (TB5). METHODS: Since 1996, more than 5000 consecutive probands have been referred nationwide to our laboratory for molecular diagnosis of suspected MFS. RESULTS: We identified five MFS probands carrying distinct heterozygous pathogenic in-frame variants affecting the TB5 domain of FBN1. The clinical data showed that the probands displayed a classical form of MFS. Strikingly, one missense variant affects an amino acid that was previously involved in GPHYSD. CONCLUSION: Surprisingly, pathogenic variants in the TB5 domain of FBN1 can lead to two opposite phenotypes: GPHYSD/ACMICD and MFS, suggesting the existence of different pathogenic sequences with the involvement of tissue specificity. Further functional studies are ongoing to determine the precise role of this domain in the physiopathology of each disease.

The critical role of the TB5 domain of fibrillin-1 in endochondral ossification.

Mutations in the fibrillin-1 (FBN1) gene are responsible for the autosomal dominant form of geleophysic dysplasia (GD), which is characterized by short stature and extremities, thick skin and cardiovascular disease. All known FBN1 mutations in patients with GD are localized within the region encoding the transforming growth factor-ß binding protein-like 5 (TB5) domain of this protein. Herein, we generated a knock-in mouse model, Fbn1Y1698C by introducing the p.Tyr1696Cys mutation from a patient with GD into the TB5 domain of murine Fbn1 to elucidate the specific role of this domain in endochondral ossification. We found that both Fbn1Y1698C/+ and Fbn1Y1698C/Y1698C mice exhibited a reduced stature reminiscent of the human GD phenotype. The Fbn1 point mutation introduced in these mice affected the growth plate formation owing to abnormal chondrocyte differentiation such that mutant chondrocytes failed to establish a dense microfibrillar network composed of FBN1. This original Fbn1 mutant mouse model offers new insight into the pathogenic events underlying GD. Our findings suggest that the etiology of GD involves the dysregulation of the extracellular matrix composed of an abnormal FBN1 microfibril network impacting the differentiation of the chondrocytes.

Cooperative Mechanism of ADAMTS/ ADAMTSL and Fibrillin-1 in the Marfan Syndrome and Acromelic Dysplasias.

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 TGFß-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.

ADAMTS Proteins and Vascular Remodeling in Aortic Aneurysms.

Extracellular matrix (ECM) in the vascular wall is a highly dynamic structure composed of a set of different molecules such as elastins, collagens, fibronectin (Fn), laminins, proteoglycans, and polysaccharides. ECM undergoes remodeling processes to regulate vascular smooth muscle and endothelial cells' proliferation, differentiation, and adhesion. Abnormalities affecting the ECM can lead to alteration in cellular behavior and from this, this can conduce to the development of pathologies. Metalloproteases play a key role in maintaining the homeostasis of ECM by mediating the cleavage of different ECM components. There are different types of metalloproteases: matrix metalloproteinases (MMPs), disintegrin and metalloproteinases (ADAMs), and ADAMs with thrombospondin motifs (ADAMTSs). ADAMTSs have been found to participate in cardiovascular physiology and diseases and specifically in aortic aneurysms. This review aims to decipher the potential role of ADAMTS proteins in the physiopathologic development of Thoracic Aortic Aneurysms (TAA) and Abdominal Aortic Aneurysms (AAA). This review will focus on what is known on the ADAMTS family involved in human aneurysms from human tissues to mouse models. The recent findings on THSD4 (encoding ADAMTSL6) mutations in TAA give a new insight on the involvement of the ADAMTS family in TAA.