A Novel Heterozygous Intronic Mutation in the FBN1 Gene Contributes to FBN1 RNA Missplicing Events in the Marfan Syndrome
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A Novel Heterozygous Intronic Mutation in the FBN1 Gene Contributes to FBN1 RNA Missplicing Events in the Marfan SyndromeAuthor(s)
Date
2018Citation
Torrado M, Maneiro E, Trujillo-Quintero JO, Evangelista A, Mikhailov AT, Monserrat L. A novel heterozygous intronic mutation in the FBN1 gene contributes to FBN1 RNA missplicing events in the Marfan syndrome. BioMed Res Int. 2018;2018:3536495
Abstract
[Abstract] 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.
Keywords
Aorta surgery
Marfan syndrome
Gene expression
Mutation (Biology)
Polymerase chain reaction
RNA
Western immunoblotting
Fibrillin
Dilatation & curettage
Sequence analysis
Marfan syndrome
Gene expression
Mutation (Biology)
Polymerase chain reaction
RNA
Western immunoblotting
Fibrillin
Dilatation & curettage
Sequence analysis
Editor version
Rights
Atribución 4.0 Internacional (CC BY 4.0)
ISSN
2314-6141
2314-6133
2314-6133