The fibrillinopathies: New insights with focus on the paradigm of opposing phenotypes for both FBN1 and FBN2

Abstract

Different pathogenic variants in the fibrillin-1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias. Whereas the musculoskeletal features of Marfan syndrome involve tall stature, arachnodactyly, joint hypermobility, and muscle hypoplasia, acromelic dysplasia patients present with short stature, brachydactyly, stiff joints, and hypermuscularity. Similarly, pathogenic variants in the fibrillin-2 gene (FBN2) cause either a Marfanoid congenital contractural arachnodactyly or a FBN2-related acromelic dysplasia that most prominently presents with brachydactyly. The phenotypic and molecular resemblances between both the FBN1 and FBN2-related disorders suggest that reciprocal pathomechanistic lessons can be learned. In this review, we provide an updated overview and comparison of the phenotypic and mutational spectra of both the "tall" and "short" fibrillinopathies. The future parallel functional study of both FBN1/2-related disorders will reveal new insights into how pathogenic fibrillin variants differently affect the fibrillin microfibril network and/or growth factor homeostasis in clinically opposite syndromes. This knowledge may eventually be translated into new therapeutic approaches by targeting or modulating the fibrillin microfibril network and/or the signaling pathways under its control.

A patient with pleuroparenchymal fibroelastosis carrying a novel fibrillin-2 gene variant

“…The diagnosis of CCA is established with suggestive findings and heterozygous FBN2 pathogenic variants identified by molecular testing [ 2 ]. However, fibrillin genes variants shows various clinical phenotype without marfanoid features or classical features without FBN2 gene mutation [ 5 ]. Especially, the occurrence of FBN2 related disorder make it more difficult for it to be diagnosed because some of the features either improve or are overlooked in infant, thus, the need to prove the FBN2 mutation is crucial.…”

“…In developmental lung, FBN2 occurs earlier and is a stronger inducer of elastin synthesis than FBN1, furthermore, it is buried within the postnatal microfibrils and may be unrecognized in the postnatal period [ 12 ]. Fibrillin also regulates transforming growth factor -β(TGF-β)by sequestration of the extracellular matrix, through binding to other protein such as the latent TGF-β binding proteins 4 (LTBP-4) [ 5 ]. Elevated LTBP-4 has previously been reported in PPFE patients [ 13 ].…”

Structural genomic variants in thoracic aortic disease

“…In this paediatric cohort, 5% of patients harboured a pathogenic CNV in FBN1 . FBN1 encodes fibrillin-1 that functions as a structural component in the extracellular matrix and regulates growth factor signalling pathways [ 20 ]. A study by Yamaguchi et al [ 21 ] identified one multiexon deletion of COL3A1 (alpha 1 chain of type III collagen) in a patient with vascular Ehlers-Danlos syndrome (vEDS; MIM #130050).…”

Clinical and genetic screening in a large Iranian family with Marfan syndrome: A case study

“…FBN1 plays an important role in the stability and strength of these tissues 8 . Microfibril production is disrupted by pathogenic FBN1 variants, which also cause abnormal fibrillin protein formation and ultimately impair connective tissue 9 …”

“…8 Microfibril production is disrupted by pathogenic FBN1 variants, which also cause abnormal fibrillin protein formation and ultimately impair connective tissue. 9 Here, we characterized the phenotype and determined the genetic etiology of a large Iranian family with symptoms consistent with MFS using molecular diagnostic methods. Through whole exome sequencing (WES) and bioinformatics analysis, a heterozygous missense pathogenic variant (c.2179T>C) in FBN1 gene was detected in the proband and affected family members.…”