Novel exon nucleotide substitution at the splice junction causes a neonatal Marfan syndrome

S. C. Chao, J. S. Chen, C. H. Tsai, J. Y.M. Lin, Y. J. Lin, H. S. Sun

Research output: Contribution to journalComment/debatepeer-review

10 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)453-463
Number of pages11
JournalClinical Genetics
Issue number5
Publication statusPublished - 2010 May

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


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