Torrado, MarioManeiro, EmiliaTrujillo-Quintero, Juan PabloEvangelista, ArturoMikhailov, Alexander T.Monserrat, Lorenzo2018-06-262018-06-262018Torrado 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;2018:35364952314-61412314-6133http://hdl.handle.net/2183/20817[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.engAtribución 4.0 Internacional (CC BY 4.0)https://creativecommons.org/licenses/by/4.0/Aorta surgeryMarfan syndromeGene expressionMutation (Biology)Polymerase chain reactionRNAWestern immunoblottingFibrillinDilatation & curettageSequence analysisjournal articleopen access