The Biology of Marfan Syndrome

Abstract

Marfans syndrome (MFS) is a connective tissue disorder, affecting multiple organ systems around the body, leading to a large variety of symptoms. It is an incurable disease, with symptoms commonly occurring during puberty, neonatal Marfan syndrome is an exception to this as symptoms are present at birth. The disease is caused by over a thousand different mutations, making genotype-phenotype correlations challenging. The most common symptoms include cardiovascular manifestations, skeletal systems involvement and ocular manifestations. The involvement of the aorta is the leading cause of death in MFS patients, but this manifestation can be treated with beta blockers, increasing life expectancy and quality of life. FBN1 is the causative gene of MFS, it encodes the fibrillin-1 protein meaning MFS patients have lower levels of fibrillin-1. This reduces the amount of microfibrils available in the extracellular matrix increasing the amount of transforming growth factor  signalling.

Introduction

Marfans syndrome (MFS) is a connective tissue disorder caused by a mutation in the fibrillin 1 (FBN1) protein. It occurs in approximately 1 in 5000 individuals, with no correlation to either gender or race (1). The disease predominantly effects the heart, blood vessels, skeleton and ocular systems as these organs are reliant on microfibrils formed by fibrillin-1 for normal functioning. MFS is characterised by tall individuals with long limbs, fingers and toes. 75% of the time MFS is inherited as an autosomal dominant disorder (2), so one copy of the mutated gene in each cell will cause MFS, the other 25% of the time the disease is caused by a random mutation. The mutated FBN1 has phenotypic variance, making early diagnosis difficult as different patients symptoms vary extensively. Most manifestations of the disease occur during puberty; neonatal Marfans syndrome (nMFS) is an exception to this and symptoms are often present at birth, making nMFS a more serious strain of the disease (2). Diagnosis of MFS relies on a multidisciplinary team of healthcare professionals and the ghent nonsology is commonly used to determine if the patient has the disease(2).

Structure and function of fibrillin-1

Fibrillin-1 is made from the FBN1 gene, located on chromosome 15 (3). It consists of various repeated domains containing 47 Epidermal Growth Factor like domains (shown in figure 1). Each domain contains 6 cysteine residues, 43 out of the 47 domains contain a calcium binding sequence (3).