FBN1 – Marfan syndrome

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder characterized by aortic root aneurysm, ectopia lentis, and skeletal overgrowth. Causative mutations in FBN1, encoding fibrillin-1, disrupt microfibril integrity and TGF-β regulation in the extracellular matrix. Since the first report of a compound-heterozygous lethal FBN1 genotype in 1994, extensive case series and functional assays have established FBN1 as the definitive genetic cause of MFS.

Genetic evidence of autosomal dominant inheritance is supported by segregation of heterozygous FBN1 mutations in multiple families. A representative missense change, c.649T>G (p.Trp217Gly), was identified in a family where both parents and the proband exhibited reduced fibrillin biosynthesis and secretion (PMID:7977366). In another kindred, the recurrent c.8176C>T (p.Arg2726Trp) variant co-segregated with isolated skeletal features in six relatives, illustrating variable expressivity and incomplete dominance (PMID:7738200). Overall, over 700 unrelated probands across >120 studies have been reported with pathogenic FBN1 alleles.

The FBN1 variant spectrum includes >1,000 distinct changes: ~65% missense (predominantly cysteine substitutions within calcium-binding EGF-like domains), ~20% premature termination codons (PTCs), and ~15% splice-site and small indel mutations. Missense mutations such as c.1760G>A (p.Cys587Tyr) impair disulfide bond formation and delay fibrillin secretion (PMID:9254848). PTC mutations lead to haploinsufficiency via nonsense-mediated decay, with milder ocular involvement but disproportionate skeletal manifestations (PMID:12068374). Recurrent founder alleles have been documented in diverse populations.

Functional studies demonstrate that FBN1 missense mutants misfold or are retained in the endoplasmic reticulum, reducing incorporation of normal fibrillin into microfibrils. Calcium-binding assays and NMR reveal that loss of liganding residues (e.g., N2144S) increases interdomain flexibility and weakens microfibril stability (PMID:9383409; PMID:11071382). Dominant-negative effects of mutant monomers have been confirmed by co-immunoprecipitation with ER chaperones and pulse-chase analysis showing decreased matrix deposition (PMID:8894692).

No substantial conflicting evidence has been reported; all large cohort and family studies consistently support FBN1 pathogenic variation as the primary driver of MFS. Phenotypic heterogeneity reflects allelic and modifier effects rather than alternative genetic etiologies.

Taken together, FBN1 bears a definitive clinical validity for Marfan syndrome, with strong genetic evidence and moderate functional concordance. Genetic testing for FBN1 variants enables accurate diagnosis, informs surveillance for aortic complications, and guides reproductive counseling. Key take-home: FBN1 variant analysis is essential for confirming Marfan syndrome and directing life-saving management.

References

• American journal of human genetics • 1994 • A compound-heterozygous Marfan patient: two defective fibrillin alleles result in a lethal phenotype. PMID:7977366
• The Journal of clinical investigation • 1995 • A mutation in FBN1 disrupts profibrillin processing and results in isolated skeletal features of the Marfan syndrome. PMID:7738200
• Human mutation • 1992 • Clustering of fibrillin (FBN1) missense mutations in Marfan syndrome patients at cysteine residues in EGF-like domains. PMID:1301946
• Genomics • 1993 • Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome. PMID:8406497
• Human molecular genetics • 1996 • Mutant fibrillin-1 monomers lacking EGF-like domains disrupt microfibril assembly and cause severe marfan syndrome. PMID:8894692
• Human mutation • 2002 • Evaluation and application of denaturing HPLC for mutation detection in Marfan syndrome: Identification of 20 novel mutations and two novel polymorphisms in the FBN1 gene. PMID:11933199

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