Fibrillines et fibrillinopathies

Abstract

Les fibrillines sont les constituants majeurs du réseau microfibrillaire. Cette structure du tissu conjonctif est, soit étroitement associée aux fibres d'élastine, soit présente en agrégats isolés dans les tissus dépourvus d'élastine. Les travaux de biologie cellulaire et moléculaire ont permis d'élucider la structure des fibrillines et de commencer à appréhender leurs relations avec les autres constituants de la matrice extracellulaire. Mais, c'est la description de leur altération dans différentes maladies du tissu conjonctif, dont le syndrome de Marfan, qui a révélé leur importance.

Microfibrils contain a variety of proteins, the most prominent of which are the two fibrillins. Fibrillins are large glycoproteins (320 kDa) ubiquitously distributed in connective tissues. Together with amorphous elastin, fibrillin-containing microfibrils form the elastic fibers. Fibrillins are also found in microfibrils that are apparently unendowed with amorphous elastin, such as those forming the ciliary zonule. Fibrillins are encoded by two different genes: FBN1 on human chromosome 15q21 encodes type 1 fibrillin and FBN2 on human chromosome 5q23 encodes type 2 fibrillin. The most notable structural feature of these proteins is the presence of numerous calcium-binding epidermal growth-factor-like motifs interspersed with a few motifs homologous to those found in the binding protein for transforming growth factor beta. The study of the developmental expression of the fibrillin genes has revealed different patterns: FBN1 is mainly expressed during late morphogenesis while FBN2 expression coincides with early morphogenesis and notably the beginning of elastogenesis. Therefore, fibrillins could contribute to the structural and functional heterogeneity of microfibrils. This heterogeneity is reflected in the large phenotypic spectrum associated with mutations in the fibrillin genes. These mutations are found in a new group of inherited connective-tissue disorders: the fibrillinopathies. To date, 76 mutations have been identified in the FBN1 gene. These mutations are associated not only with the Marfan syndrome (MFS) but also with a spectrum of conditions phenotypically related to MFS including dominantly inherited ectopia lentis, severe neonatal Marfan syndrome and isolated typical features of Marfan syndrome. Conversely, only a few mutations have been reported in the FBN2 gene and they are observed in congenital contractural arachnodactyly. Important issues that will now have to be addressed concern the elucidation of the exact composition of the microfibrils and their spatial organization into tissue-specific macro-aggregates.