A Novel Heterozygous Intronic Mutation in the FBN1 Gene Contributes to FBN1 RNA Missplicing Events in the Marfan Syndrome

Biomed Res Int. 2018 May 29;2018:3536495. doi: 10.1155/2018/3536495. eCollection 2018.


Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder, mostly caused by mutations in the fibrillin-1 (FBN1) gene. We, by using targeted next-generation sequence analysis, identified a novel intronic FBN1 mutation (the c.2678-15C>A variant) in a MFS patient with aortic dilatation. The computational predictions showed that the heterozygous c.2678-15C>A intronic variant might influence the splicing process by differentially affecting canonical versus cryptic splice site utilization within intron 22 of the FBN1 gene. RT-PCR and Western blot analyses, using FBN1 minigenes transfected into HeLa and COS-7 cells, revealed that the c.2678-15C>A variant disrupts normal splicing of intron 22 leading to aberrant 13-nt intron 22 inclusion, frameshift, and premature termination codon. Collectively, the results strongly suggest that the c.2678-15C>A variant could lead to haploinsufficiency of the FBN1 functional protein and structural connective tissue fragility in MFS complicated by aorta dilation, a finding that further expands on the genetic basis of aortic pathology.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Aorta / pathology
  • Dilatation, Pathologic
  • Fibrillin-1 / genetics*
  • Heterozygote
  • Humans
  • Introns / genetics*
  • Male
  • Marfan Syndrome / genetics*
  • Microfilament Proteins
  • Mutation*


  • FBN1 protein, human
  • Fibrillin-1
  • Microfilament Proteins