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Fibrillin-1 (FBN1) gene frameshift mutations in Marfan patients: genotype-phenotype correlation
G Pepe1, B Giusti, L Evangelisti
1Dipartimento di Area Critica Medico Chirurgica, sezione Clinica Medica Generale e Cliniche Specialistiche, University of Florence, Viale Morgagni 85, 50134, Florence, Italy. labctrombosi@ao-careggi.toscana.it
Abstract:
Marfan syndrome (MFS) is a multisystemic disease associated with mutations in the fibrillin-1 gene. Most of the reported mutations are missense substitutions mainly affecting the epidermal growth factor (EGF)-like protein domain structure and the calcium-binding (cb) site. The aim of our study was to investigate the correlation between fibrillin-1 frameshift mutations and the clinical phenotype in patients affected by MFS. In 48 out of 66 Marfan patients a pathogenetic mutation was found. We detected novel mutations causing premature termination codon in exons 19, 37, 40 and 41 of four Italian patients. The first mutation in exon 19 (cbEGF #8 domain) results in a clinical phenotype involving mainly the skeletal and cardiovascular systems. Interestingly, we noticed that, while mutations in exons 37 and 41 (eight cysteine domains #4 and #5) are milder, the mutation in exon 40 (cbEGF #24 domain) is more severe and causes major cardiovascular involvement with thoracic and abdominal aortic aneurysms. It is noteworthy that the degree of the severity in the phenotype of one of our patients and another from the literature carrying a mutation in exon 41 could be explained with alterations in mRNA expression.
Insights
Marfan syndrome (MFS) is linked to fibrillin-1 gene mutations. Frameshift mutations in specific exons correlate with varying clinical severity, particularly cardiovascular impact, offering insights into MFS progression.
Area of Science:
- Genetics
- Molecular Biology
- Medical Science
Background:
- Marfan syndrome (MFS) is a genetic disorder affecting connective tissue, primarily caused by mutations in the fibrillin-1 gene.
- Most known mutations are missense substitutions impacting protein structure, particularly EGF-like domains and calcium-binding sites.
Observation:
- This study investigated frameshift mutations in the fibrillin-1 gene in Marfan syndrome patients.
- Novel mutations leading to premature termination codons were identified in exons 19, 37, 40, and 41 in four Italian patients.
Findings:
- A mutation in exon 19 (cbEGF #8) primarily affected skeletal and cardiovascular systems.
- Mutations in exons 37 and 41 (cysteine domains #4 and #5) showed milder phenotypes, whereas exon 40 (cbEGF #24) mutation resulted in severe cardiovascular issues, including aortic aneurysms.
- Phenotype severity, especially for exon 41 mutations, may be linked to altered mRNA expression levels.
Implications:
- Frameshift mutations in fibrillin-1 gene contribute to Marfan syndrome's diverse clinical spectrum.
- Understanding genotype-phenotype correlations, including the impact of specific exon mutations and mRNA expression, is crucial for predicting MFS progression and patient outcomes.
- This research highlights the importance of identifying novel mutations for a comprehensive understanding of Marfan syndrome.