Microfibrils are suggested to determine the form and the orientation of elastic fibers, thus directing fiber assembly as a scaffold on which elastin is deposited. This model explains the typical fragmentation and disarray of elastic fibers observed in the media of Marfan patients. However, unlike elastin, fibrillin-1 is also highly expressed in the vascular adventitia. Therefore reduction of this protein in the adventia is very likely also involved in the mechanism for dilatation and for increased risk of aneurysm because the role of the adventia is to maintain the vascular diameter. The pleiotropic manifestations of the disease can be explained by the observation that numerous microfibrillar aggregates devoid of elastin are found in the zonule, as well as cartilage and the extracellular matrix of many organs. However, the actual pathogenic mechanisms in these tissues still remain speculative.
At the molecular level, two different groups of mutations are distinguishable: mutations leading to a shortened protein and missense mutations. The first group corresponds to one third of the mutations. They can be responsible for: 1) the appearance of a premature stop codon that reduces the stability of the mutant transcript and, consequently, greatly reduces protein production from the mutated copy of the gene (in the affected subjects, the amount of fibrillin-1 protein produced is 50% that of normal and is produced only from the normal gene copy), or, 2) the production from the mutated copy of an abnormal monomer that considerably interferes with the assembly (polymerization) of fibrillin molecules (the amount of fibrillin is greatly reduced, <35%). The second group represent two thirds of mutations and corresponds to missense mutation. Among them, three quarters are located in calcium-binding modules. They are implicated either in creating or substituting cysteine residues potentially implicated in disulfide bonding and, consequently, in the correct folding of the monomer. The majority of remaining mutations of this type of module affect residues of the calcium consensus sequence that playa major role in defining interdomain linkage. An increased protease susceptibility is a mechanism also suggested for missense mutations. Other modules are carriers of one quarter of missense mutations and pathological mechanisms have yet to be clearly demonstrated.
What is still unknown are the multiple consequences triggered by the various mutations and the effects of unknown modifier (enhancing or protecting) genes on clinical expression. These mechanisms and the great number of mutations identified in the FBN1 gene explain the great variability of the disease observed not only between families but also among affected individuals in a single family.
Was this article helpful?
The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.