Molecular Genetics of the Fibrillinopathies

Abstract

Abstract Fibrillins are major glycoprotein components of microfibrils in the extracellular matrix. They are polymerised in a complex beads‐on‐a‐string appearance and form isolated aggregates or are closely associated with elastin in elastic fibres. Fibrillins are critical actors of the biomechanical function of connective tissue and regulators of the bioavailability of signalling molecules, especially TGF‐β. Mutations in the FBN1 and FBN2 genes are associated with inherited diseases now termed fibrillinopathies. These diseases represent a wide spectrum of disorders including Marfan and neonatal Marfan syndrome, acromelic dysplasias, progeroid‐marfanoid syndrome, the stiff skin syndrome and congenital contractural arachnodactyly. Clinical symptoms are varied, thus highlighting the importance of fibrillins in tissue development and integrity. The identification of over 3000 mutations in FBN1 and over 100 in FBN2 has provided only a few instances of genotype–phenotype correlations but have provided clues in the functional role of fibrillin domains. Key Concepts Fibrillin is a structural component of the extracellular matrix but is involved in cytokine signalling through its role of a niche for inactive procytokines. There are three fibrillin genes encoding fibrillins 1, 2 and 3 that all share a conserved modular domain organisation with various degrees of homology. Marfan syndrome is a highly variable and rare autosomal dominant disease with plurisystemic features and life‐threatening vascular complications. Marfan syndrome is mostly associated with mutations in the FBN1 gene with no clear genotype/phenotype correlation, thus undescoring the existence of genetic modifiers that underlie clinical variability. Acromelic and geleophysic dysplasias, stiff skin syndrome and progeroid syndrome also display mutations in the FBN1 gene, constituting with Marfan syndrome the group of type 1 fibrillinopathies. Contrary to Marfan syndrome, all other type 1 fibrillinopathies are associated with mutations in specific domains of the protein. Mutations in the FBN2 gene are found in congenital contractural arachnodactyly. No disease‐related mutation has been reported yet in the FBN3 gene. Eighteen spontaneous, radiation‐induced or transgenic mice models with mutations in the FBN1 and FBN2 genes are available.