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PMID: 9463322 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Nearby stop codons in exons of the neurofibromatosis type 1 gene are disparate splice effectors.

American journal of human genetics ·Vol. 62 ·No. 2 ·1998-02-00 ·Pages 269-77

Hoffmeyer S, Nürnberg P, Ritter H, Fahsold R, Leistner W, Kaufmann D, Krone W

Abstract

Stop mutations are known to disrupt gene function in different ways. They both give rise to truncated polypeptides because of the premature-termination codons (PTCs) and frequently affect the metabolism of the corresponding mRNAs. The analysis of neurofibromin transcripts from different neurofibromatosis type 1 (NF1) patients revealed the skipping of exons containing PTCs. The phenomenon of exon skipping induced by nonsense mutations has been described for other disease genes, including the CFTR (cystic fibrosis transmembrance conductance regulator) gene and the fibrillin gene. We characterized several stop mutations localized within a few base pairs in exons 7 and 37 and noticed complete skipping of either exon in some cases. Because skipping of exon 7 and of exon 37 does not lead to a frameshift, PTCs are avoided in that way. Nuclear-scanning mechanisms for PTCs have been postulated to trigger the removal of the affected exons from the transcript. However, other stop mutations that we found in either NF1 exon did not lead to a skip, although they were localized within the same region. Calculations of minimum-free-energy structures of the respective regions suggest that both changes in the secondary structure of the mRNA and creation or disruption of exonic sequences relevant for the splicing process might in fact cause these different splice phenomena observed in the NF1 gene.

MeSH Terms
Alternative Splicing Base Sequence Codon, Terminator DNA/chemistry,genetics Exons Humans Introns Melanocytes/cytology,pathology Models, Molecular Molecular Sequence Data Mutation Neurofibromatosis 1/blood,genetics,pathology Neurofibromin 1 Nucleic Acid Conformation Polymerase Chain Reaction Protein Biosynthesis Proteins/genetics Skin/cytology,pathology Thermodynamics Transcription, Genetic
Chemicals
Codon, Terminator Neurofibromin 1 Proteins DNA
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Hoffmeyer S
Abteilung Humangenetik, Universitat Ulm, Ulm, Germany. sven.hoffmeyer@medizin.uni-ulm.de
Nürnberg P
Ritter H
Fahsold R
Leistner W
Kaufmann D
Krone W
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/301715
Email
sven.hoffmeyer@medizin.uni-ulm.de
Published
1998-02-00
Pages
269-77
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1376891
Subset
IM
External Links
PubMed source DOI: 10.1086/301715 PMC Full Text View journal details
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