Marfan Syndrome: New Clues to Genotype—Phenotype Correlations

Abstract

Fibrillin 1 is the main constituent of extracellular microfibrils. Microfibrils can exist as inividual structures or associate with elastin to form elastic fibres. Fibrillin 1 mutations are the cause of the pleiotropic manifestations of the Marfan syndrome (MFS) which principally involve the musculoskeletal, ocular and cardiovascular systems. MFS pathogenesis requires high levels of mutant fibrillin 1 molecules with dominant-negative activity on microfibrillar assembly and function. Gene-targeting experiments in the mouse have shed new light on fibrillin 1 function, genotype-phenotype correlations and aneurysm progression. These experiments have documented the involvement of fibrillin 1 in mantaining tissue homeostasis, suggested the existence of a critical threshold of functional microfibrils for tissue biomechanics, and outlined novel contributors to the pathogenic sequence of vascular wall collapse.

Key Words:

• connective tissue
• dissecting aneurysm
• elastic fibres
• elastin
• elastolysis
• homologous gene targeting
• inflammation
• Marfan syndrome
• microfibrils
• mouse models of human diseases
• vascular calcification