Potential Phenotype–Genotype Correlation in Marfan Syndrome

Abstract

A recent emphasis on individualized medicine reflects a desire to transition currently prevailing evidence-based practices (What works best for the average patient?) to more informed and tailored approaches (What will work best for this patient or subgroup?). It has been both expected and realized that genotypic information will contribute prominently to this endeavor. In this issue of Circulation Cardiovascular Genetics, Franken et al 1 report that the angiotensin receptor blocker (ARB) losartan is particularly effective at suppressing aortic root aneurysm progression in patients with Marfan syndrome (MFS) that are heterozygous for mutations in the fibrillin-1 gene (FBN1) that create a premature termination codon, when compared with other mutation classes expected to express abnormal protein from the mutant allele. Given the intuitive importance of this finding, it is worth exploring its potential biological foundations, while also considering alternative explanations. Article see p 383 Proposed Pathogenesis of MFSMFS is an autosomal-dominant systemic disorder of connective tissue with prominent involvement of the ocular, skeletal, and cardiovascular systems, including a strong predisposition for eye lens dislocation (ectopia lentis) and myopia, long-bone overgrowth and other skeletal deformity, and progressive aortic root dilatation and tear (dissection), respectively. The condition is caused by heterozygous mutations in FBN1 that encodes the extracellular matrix protein fibrillin-1. Fibrillin-1 monomers aggregate to form complex extracellular structures called microfibrils and an extracellular deficiency of microfibrils is thought to be the sentinel event in MFS pathogenesis. Missense mutations are the most common type causing MFS, with particularly high frequency of substitutions that either destroy or create cysteine residues in repetitive epidermal growth factor-like or latent transforming growth factor-β (TGF-β)-binding protein-like domains that each have 6 or 8 obligate cysteines with predictable spacing, respectively, that are required for proper intradomain folding. The FBN1 mutational repertoire also includes all other types of mutations, including insertions/deletions (indels) or altered splicing events that alter the coding sequence but maintain the open reading frame and events that create a premature termination codon, including nonsense and frameshift mutations and out-of-frame perturbations of splicing. Finally, a small subset of patients with MFS show large deletions that remove most or all of the disrupted allele. Premature termination codon mutations in FBN1 that disrupt the open reading frame before the distal portion of the penultimate are expected and observed to induce instability and efficient clearance of the mutant mRNA through nonsense-mediated mRNA decay, effectively precluding the production of much (or any) abnormal fibrillin-1 protein. Cell lines and tissues from patients and mouse models with MFS show diminished matrix deposition of fibrillin-1, with levels <50% threshold predict...

Craniofacial characterization of Marfan Syndrome

“…Studies have reported the phenotypic expression of MFS is unpredictable, which possibly explains our finding of no difference between groups . Indeed, phenotypic variation is prevalent in families with MFS carrying the same genetic mutation . While this may partly explain our findings, our small sample size is likely a contributing factor as well.…”

“…It is unknown if maxillary expansion was prescribed due to a narrow palate and/or crossbite, but one indication for maxillary expansion is a narrow palate. Staufenbiel and colleagues reported on the prevalence of orthodontic treatment among subjects with MFS and found that 62% (N = 51) had a previous history of orthodontic treatment . Orthodontic treatment is rarely indicated in the primary dentition and is not routinely recommended in the mixed dentition stage thus the youngest of our sample may not have warranted orthodontic treatment.…”

Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome

“…Efficient fibrillin-1 deposition into the matrix is reliant on a critical threshold of normal fibrillin-1 accumulation at the cell surface, and the loss of contribution from one allele is sufficient to significantly impair efficient use of protein derived from non-mutated allele. However, matrix incorporation of mutant fibrillin-1 (unique to DN-type mutations) can also promote proteolytic clearance of microfibrils over time, perhaps further exacerbating the functional deficit and contributing to phenotypic progression 13. We recently found that patients with an HI- FBN1 mutation more often have aortic dissections and shorter survival compared with those with a DN- FBN1 mutation 14…”

AT1-receptor blockade, but not renin inhibition, reduces aneurysm growth and cardiac failure in fibulin-4 mice

“…This correlates well with the widely accepted phenomenon that AT 2 Rs normally display low-to-undetectable levels, which increase only under pathological conditions, for example, postmyocardial infarction, during hypertension-induced remodeling, and in heart failure [45][46][47]. Clearly, timing of treatment is of utmost importance, and different ages at the start of treatment (e.g., children/adolescents versus adults) may explain the success (or lack thereof) of different RAS blockers in clinical trials [17,18,48]. Moreover, when classifying FBN1 mutations into 'haploinsufficiency' (decreased amount of normal fibrillin-1), and 'dominant negative' (normal fibrillin-1 abundance with mutant fibrillin-1 incorporated in the matrix), Franken et al [49] observed that Marfan patients with haploinsufficient FBN1 mutations were more responsive to losartan.…”