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

Sheau-Chiou Chao, J. S. Chen, C. H. Tsai, J. Y.M. Lin, Y. J. Lin, Hsiao-Fang Sun

研究成果: Comment/debate

7 引文 (Scopus)

摘要

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.

原文English
頁(從 - 到)453-463
頁數11
期刊Clinical Genetics
77
發行號5
DOIs
出版狀態Published - 2010 五月 1

指紋

Marfan Syndrome
Exons
Nucleotides
Mutation
Nonsense Codon
Genes
Endoplasmic Reticulum-Associated Degradation
Fibrillin-1
Phenotype
Amino Acids
Peptides
Proteins

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

引用此文

Chao, Sheau-Chiou ; Chen, J. S. ; Tsai, C. H. ; Lin, J. Y.M. ; Lin, Y. J. ; Sun, Hsiao-Fang. / Novel exon nucleotide substitution at the splice junction causes a neonatal Marfan syndrome. 於: Clinical Genetics. 2010 ; 卷 77, 編號 5. 頁 453-463.
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Novel exon nucleotide substitution at the splice junction causes a neonatal Marfan syndrome. / Chao, Sheau-Chiou; Chen, J. S.; Tsai, C. H.; Lin, J. Y.M.; Lin, Y. J.; Sun, Hsiao-Fang.

於: Clinical Genetics, 卷 77, 編號 5, 01.05.2010, p. 453-463.

研究成果: Comment/debate

TY - JOUR

T1 - Novel exon nucleotide substitution at the splice junction causes a neonatal Marfan syndrome

AU - Chao, Sheau-Chiou

AU - Chen, J. S.

AU - Tsai, C. H.

AU - Lin, J. Y.M.

AU - Lin, Y. J.

AU - Sun, Hsiao-Fang

PY - 2010/5/1

Y1 - 2010/5/1

N2 - 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.

AB - 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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