Introduction

Marfan syndrome is a genetic disorder that affects the body's connective tissues. Inside our cells, genetic information is stored in chromosomes made of DNA. These chromosomes contain genes, which provide instructions for making proteins essential for cell functions. What happens when a mutation takes place in one of these genes, and how can this mutation lead to Marfan syndrome?

Chromosomes, genes, DNA and their role in the cell

In human cells, genetic information is packaged into chromosomes [1]. These exist out of 2 long strands of DNA. A human has 46 chromosomes per cell which are divided into 23 different pairs. Each chromosome carries genes, which is a segment of DNA that contains the instruction for making a particular protein (figure 1). Each human cell contains approximately 20,000 protein-coding genes. Proteins are responsible for almost every task in a cell, such as sending messages, helping with chemical reactions and building structures.

The 2 long strands of DNA exist out of a sugar-phosphate backbone and 4 different bases. These bases are adenine, cytosine, guanine and thymine. A gene exists out of multiple of these bases combined and the exact number of bases in a gene can vary greatly depending on the gene's size and function. However, genes typically consist of hundreds to millions of bases. In a gene, bases are arranged sequentially along the DNA strand. The specific sequence of these bases is not random. Rather, it is determined by the genetic code. Each gene has a unique sequence of bases that encode the instructions for building a particular protein.

Mutations change the Genes Structure

 Marfan syndrome is caused by a mutation in the FBN1-gene [2]. The FBN1-gene codes for the protein fibrillin-1. This protein is important in the formation of microfibrils, which are small structures who help organise the arrangement of elastin within elastic fibres found in connective tissues throughout the body [3, 4]. Elastic fibres are long, thin fibres that form networks in the space outside cells [5]. Elastin allows the elastic fibres to stretch and recoil. Because of this, the connective tissue is stretchy. This way, Fibrillin-1 provides structure and elasticity to various tissues, such as arteries and veins, the skin and the lungs [3].

Sometimes, genes contain changes called mutations [1]. These changes can cause the gene's structure to be different from what it should be. When this happens, the gene might produce different proteins than normal. A mutation can lead to various outcomes. These outcomes depend on the specific gene that is affected and the function of the protein produced. In some cases, the mutation may not have any noticeable effect, while in others, it can result in diseases, syndromes or disorders. This is the case in Marfan syndrome. Most mutations are either point mutations or frameshift mutations (figure 2). Point mutations are alterations that impact a single nucleotide pair. A frameshift mutation is when bases are added or deleted from a DNA sequence. 

Marfan and Mutation

The result of a mutation in the FBN1-gene is the large decrease of microfibrils in the connective tissue of individuals with Marfan syndrome [4]. Consequences of this decrease is the weakening and structural instability of various tissues throughout the body. Tissues become more prone to injury and malfunction when there are fewer microfibrils. Fibrillin-1 also plays a big role in the regulation of the protein ‘transforming growth factor-beta’ (TGFβ) [6]. Growth factors increase the rate of protein synthesis, including structural proteins like microfibrils [1]. Specifically, TGFβ controls many cellular processes, such as cell growth and cell repair [4]. The activation of TGFβ is managed by Fibrillin-1 [6]. A mutation in the FBN1-gene might disrupt the activation process leading to dysregulated TGFβ signalling which causes inflammation and the activation of MMP-2 and MMP-9. MMP-2 and MMP-9 are enzymes which degrade the elastic fibre, leading to the degradation and remodelling of tissues.

Effect mutation on aorta

The aorta is designed to withstand mechanical forces generated by the pulsating flow of blood [4]. One of the key elements in the aortic structure are the elastic fibres which handle the stress placed on the aorta. In Marfan syndrome, there is degradation and fragmentation of the elastic fibres which lead to loss of elasticity in the aortic wall. This causes thoracic aortic disease (TAAD) to be a major concern. Progressive widening of the aorta increases the risk of aortic dissection and rupture.

Effect mutation on skeleton

A mutation in the FBN1-gene leads to overgrowth of bones and joint laxity [4]. As discussed before, fibrillin-1 manages the activation of TGF-β. A mutation in the FBN-1 gene might dysregulate the TGF-β signalling which can lead to abnormal stimulation of bone growth and overgrowth of bones by overstimulating osteoblasts [7], resulting in long limbs.