Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
31982983
DOI
10.1007/s10875-020-00753-2
PII: 10.1007/s10875-020-00753-2
Knihovny.cz E-resources
- Keywords
- Hereditary angioedema, SERPING1, donor splice site, pre-mRNA splicing, pseudoexon activation,
- MeSH
- Child MeSH
- Adult MeSH
- Exons genetics MeSH
- Hereditary Angioedema Types I and II genetics MeSH
- Complement C1 Inhibitor Protein genetics MeSH
- Introns genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- RNA Splice Sites genetics MeSH
- Adolescent MeSH
- Young Adult MeSH
- Mutation genetics MeSH
- DNA Mutational Analysis methods MeSH
- Pedigree MeSH
- Aged MeSH
- Protein Splicing genetics MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Complement C1 Inhibitor Protein MeSH
- RNA Splice Sites MeSH
PURPOSE: Hereditary angioedema (HAE) is a rare autosomal dominant life-threatening disease characterized by low levels of C1 inhibitor (type I HAE) or normal levels of ineffective C1 inhibitor (type II HAE), typically occurring as a consequence of a SERPING1 mutation. In some cases, a causal mutation remains undetected after using a standard molecular genetic analysis. RESULTS: Here we show a long methodological way to the final discovery of c.1029 + 384A > G, a novel deep intronic mutation in intron 6 which is responsible for HAE type I in a large family and has not been identified by a conventional diagnostic approach. This mutation results in de novo donor splice site creation and subsequent pseudoexon inclusion, the mechanism firstly described to occur in SERPING1 in this study. We additionally discovered that the proximal part of intron 6 is a region potentially prone to pseudoexon-activating mutations, since natural alternative exons and additional cryptic sites occur therein. Indeed, we confirmed the existence of at least two different alternative exons in this region not described previously. CONCLUSIONS: In conclusion, our results suggest that detecting aberrant transcripts, which are often low abundant because of nonsense-mediated decay, requires a modified methodological approach. We suggest SERPING1 intron 6 sequencing and/or tailored mRNA analysis to be routinely used in HAE patients with no mutation identified in the coding sequence.
Central European Institute of Technology Masaryk University Brno Czech Republic
Centre for Cardiovascular Surgery and Transplantation Brno Czech Republic
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Mol Cell Biol. 2000 Sep;20(17):6414-25 PubMed
Ann Allergy Asthma Immunol. 2014 May;112(5):413-8 PubMed
Ann Hum Genet. 2014 Mar;78(2):73-82 PubMed
J Med Genet. 2005 Oct;42(10):737-48 PubMed
Sci Rep. 2016 Sep 09;6:32819 PubMed
J Clin Invest. 1995 Jan;95(1):350-9 PubMed
Nat Genet. 2002 Apr;30(4):426-9 PubMed
J Clin Endocrinol Metab. 2010 Jul;95(7):3542-6 PubMed
Nucleic Acids Res. 2010 Nov;38(20):7273-85 PubMed
Elife. 2016 Jul 29;5: PubMed
Biochem J. 1982 Jan 1;201(1):61-70 PubMed
PLoS Comput Biol. 2009 Mar;5(3):e1000300 PubMed
Am J Hum Genet. 2013 Jan 10;92(1):131-6 PubMed
Proc Natl Acad Sci U S A. 1986 May;83(10):3161-5 PubMed
Mol Immunol. 2011 Oct;49(1-2):18-27 PubMed
J Comput Biol. 2004;11(2-3):377-94 PubMed
PLoS One. 2011;6(5):e20036 PubMed
FEBS J. 2010 Feb;277(4):841-55 PubMed
Genet Med. 2014 Jan;16(1):101-16 PubMed
Cytogenet Genome Res. 2008;121(3-4):181-8 PubMed
Am J Hum Genet. 2017 May 4;100(5):751-765 PubMed
PLoS One. 2013;8(2):e56712 PubMed
Hum Mutat. 2002 Apr;19(4):461 PubMed
Allergy. 2014 May;69(5):602-16 PubMed
PLoS One. 2015 Jul 08;10(7):e0131637 PubMed
Allergy. 2011 Jan;66(1):76-84 PubMed
Clin Cancer Res. 2012 Sep 15;18(18):4903-9 PubMed
J Immunol. 2015 Oct 15;195(8):3596-604 PubMed
PLoS Pathog. 2016 Jun 29;12(6):e1005705 PubMed
Genome Res. 2005 Jun;15(6):768-79 PubMed
Gene. 2018 Aug 15;667:76-82 PubMed
Mol Cell Biol. 2000 Sep;20(18):6816-25 PubMed
Eur J Biochem. 1991 Apr 23;197(2):301-8 PubMed
Eur J Hum Genet. 2013 Jul;21(7):774-8 PubMed
Mol Immunol. 2008 Aug;45(13):3536-44 PubMed
J Clin Invest. 1982 Feb;69(2):462-8 PubMed
Genet Med. 2015 May;17(5):405-24 PubMed
Genes Dev. 2007 Aug 1;21(15):1833-56 PubMed
Hum Mutat. 2001;17(1):61-70 PubMed
Clin Exp Immunol. 2017 Jun;188(3):430-436 PubMed
J Clin Endocrinol Metab. 2015 Feb;100(2):E350-4 PubMed
J Mol Med (Berl). 2017 Mar;95(3):299-309 PubMed
Nucleic Acids Res. 2004 Mar 19;32(5):1783-91 PubMed
Genes Dev. 2004 Jun 1;18(11):1241-50 PubMed
Nucleic Acids Res. 2009 May;37(9):e67 PubMed
Gut. 2002 Jun;50(6):845-50 PubMed
Blood. 1986 Jul;68(1):239-43 PubMed
Adv Immunol. 2014;121:41-89 PubMed
Allergy. 2012 Nov;67(11):1430-6 PubMed
Hum Mutat. 2010 Apr;31(4):437-44 PubMed
Clin Immunol. 2014 Feb;150(2):143-8 PubMed
Hum Mutat. 2020 Jan;41(1):38-57 PubMed
Medicine (Baltimore). 1992 Jul;71(4):206-15 PubMed
J Clin Immunol. 2018 Apr;38(3):294-299 PubMed
Mol Immunol. 2019 Mar;107:91-96 PubMed
Hum Mutat. 2006 Mar;27(3):295-6 PubMed
SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAE
