FBN1-related connective tissue disorders: unraveling cardiovascular, skeletal, and ocular complications through TGF-β signaling dysregulation and genotypic correlations

Fibrillin-1 is an extracellular matrix glycoprotein essential for microfibril integrity, mediating cell-matrix interactions, providing structural support to tissues, and serving as a scaffold for elastogenesis. Pathogenic variants in the fibrillin 1 gene ( FBN1 ) give rise to a spectrum of autosomal dominant connective tissue disorders collectively termed type-1 fibrillinopathies, which include Marfan syndrome, geleophysic dysplasia 2, acromicric dysplasia, Weill-Marchesani syndrome 2, marfanoid-progeroid-lipodystrophy syndrome, stiff skin syndrome, MASS syndrome, and isolated ectopia lentis 1. These disorders predominantly manifest cardiovascular, skeletal, and ocular abnormalities. Among these, aortic and valvular lesions are the principal and most life-threatening complications and therefore warrant the greatest clinical attention. Skeletal anomalies are diverse and can even be diametrically opposed across different phenotypes, while ectopia lentis represents the hallmark of ocular conditions. Notably, mutant fibrillin-1 disrupts microfibril structure and/or function, leading to dysregulated transforming growth factor-β (TGF-β) signaling, which is widely recognized as a central mechanism underlying type-1 fibrillinopathies. Although numerous pathogenic FBN1 variants have been identified, the knowledge of genotype-phenotype correlations remains limited in some specific regions. This review synthesizes the current understanding of the FBN1 -related molecular mechanisms linking aberrant TGF-β signaling to distinct phenotypic outcomes and discusses how genetically engineered animal models and human induced pluripotent stem cell models advance mechanistic insights and facilitate therapy development. Additionally, clinical manifestations and genetic characteristics across all phenotypes are elaborated to facilitate diagnosis, treatment, and management of these complex disorders.