Chao S-C, Chen J-S, Tsai C-H, Lin JY-M, Lin Y-J, Sun HS. Novel exon nucleotide substitution at the splice junction causes a neonatal Marfan syndrome. The fibrillin-1 gene (FBN1) mutations are associated with a broad spectrum of disorders including Marfan syndrome (MFS) and show great clinical heterogeneity. An underrepresentation for mutations leading to premature termination codon (PTC) in FBN1 exons 24–32 was found in neonatal or severe MFS but the underlying cause was unclear. This study thoroughly examined two FBN1 mutations on exons 24–32 region to illustrate the molecular mechanisms underlying these FBN1 mutations on MFS etiology. Two nucleotide substitutions, c.3208G> C, the last nucleotide of exon 26, and c.3209A>G, the first nucleotide of exon 27, affecting the same amino acid, p.D1070H and p.D1070G, respectively, gave very different phenotypes. We demonstrate that c.3208G>C generates two alternatively spliced transcripts, while c.3209A>G does not affect the splicing. We further demonstrate that the aberrantly spliced transcripts do not go through nonsense-mediated decay, but rather produce unstable, premature protein peptides that are degraded by endoplasmic reticulum associated degradation. The molecular mechanism outlined here defines a model for the pathogenesis of PTC-containing mutation within the exons 24–32 of FBN1 in MFS. Furthermore, our data suggest that PTC mutation within this region may lead to early lethality in neonatal MFS.
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