The position of nonsense mutations can predict the phenotype severity: A survey on the DMD gene.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
30
04
2020
accepted:
03
08
2020
entrez:
20
8
2020
pubmed:
20
8
2020
medline:
21
10
2020
Statut:
epublish
Résumé
A nonsense mutation adds a premature stop signal that hinders any further translation of a protein-coding gene, usually resulting in a null allele. To investigate the possible exceptions, we used the DMD gene as an ideal model. First, because dystrophin absence causes Duchenne muscular dystrophy (DMD), while its reduction causes Becker muscular dystrophy (BMD). Second, the DMD gene is X-linked and there is no second allele that can interfere in males. Third, databases are accumulating reports on many mutations and phenotypic data. Finally, because DMD mutations may have important therapeutic implications. For our study, we analyzed large databases (LOVD, HGMD and ClinVar) and literature and revised critically all data, together with data from our internal patients. We totally collected 2593 patients. Positioning these mutations along the dystrophin transcript, we observed a nonrandom distribution of BMD-associated mutations within selected exons and concluded that the position can be predictive of the phenotype. Nonsense mutations always cause DMD when occurring at any point in fifty-one exons. In the remaining exons, we found milder BMD cases due to early 5' nonsense mutations, if reinitiation can occur, or due to late 3' nonsense when the shortened product retains functionality. In the central part of the gene, all mutations in some in-frame exons, such as in exons 25, 31, 37 and 38 cause BMD, while mutations in exons 30, 32, 34 and 36 cause DMD. This may have important implication in predicting the natural history and the efficacy of therapeutic use of drug-stimulated translational readthrough of premature termination codons, also considering the action of internal natural rescuers. More in general, our survey confirm that a nonsense mutation should be not necessarily classified as a null allele and this should be considered in genetic counselling.
Identifiants
pubmed: 32813700
doi: 10.1371/journal.pone.0237803
pii: PONE-D-20-12612
pmc: PMC7437896
doi:
Substances chimiques
Codon, Nonsense
0
Dystrophin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0237803Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Orphanet J Rare Dis. 2017 Aug 31;12(1):149
pubmed: 28859693
Hum Mutat. 2007 Feb;28(2):183-95
pubmed: 17041906
Clin Chem. 2008 Jun;54(6):973-81
pubmed: 18403565
PLoS One. 2013;8(3):e59916
pubmed: 23536893
Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2331-5
pubmed: 1549596
Sci Rep. 2017 Jan 03;7:39094
pubmed: 28045018
J Med Genet. 2016 Mar;53(3):145-51
pubmed: 26754139
J Mol Diagn. 2010 Jan;12(1):65-73
pubmed: 19959795
BMC Bioinformatics. 2018 Dec 12;19(1):477
pubmed: 30541431
Lancet Neurol. 2018 Mar;17(3):251-267
pubmed: 29395989
Hum Mol Genet. 1994 Oct;3(10):1907-8
pubmed: 7849724
J Neuromuscul Dis. 2018;5(4):481-495
pubmed: 30320597
Nat Med. 1996 Apr;2(4):467-9
pubmed: 8597960
Clin Genet. 2005 Jul;68(1):69-79
pubmed: 15952989
Neurogenetics. 2005 Feb;6(1):29-35
pubmed: 15655674
Curr Opin Neurol. 2009 Oct;22(5):532-8
pubmed: 19745732
Science. 1988 Nov 4;242(4879):755-9
pubmed: 3055295
Front Genet. 2020 Mar 03;11:131
pubmed: 32194622
Neuromuscul Disord. 2009 Nov;19(11):749-53
pubmed: 19783145
Acta Myol. 2012 Dec;31(3):196-200
pubmed: 23620651
Hum Mutat. 2009 Dec;30(12):1657-66
pubmed: 19937601
Brain Dev. 2018 Oct;40(9):837-840
pubmed: 29778277
Am J Hum Genet. 1995 Jan;56(1):158-66
pubmed: 7825572
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Clin Genet. 2017 Aug;92(2):199-203
pubmed: 28116794
Chin Med J (Engl). 2006 Jul 5;119(13):1079-87
pubmed: 16834926
Hum Mol Genet. 1992 Oct;1(7):517-20
pubmed: 1307253
Hum Genet. 2009 Aug;126(2):338
pubmed: 19694014
Muscle Nerve. 2006 Aug;34(2):135-44
pubmed: 16770791
Hum Mutat. 2011 Mar;32(3):299-308
pubmed: 21972111
Nat Struct Mol Biol. 2009 Feb;16(2):107-13
pubmed: 19190664
Mol Ther. 2011 May;19(5):830-40
pubmed: 21468001
Neurology. 2016 Jul 5;87(1):71-6
pubmed: 27281536
Acta Myol. 2006 Jun;25(1):5-12
pubmed: 17039975
Biochim Biophys Acta. 2015 Apr;1852(4):585-93
pubmed: 25086336
Neurol Clin. 2014 Aug;32(3):671-88, viii
pubmed: 25037084
Hum Mutat. 2009 Apr;30(4):633-40
pubmed: 19206170
Am J Med Genet C Semin Med Genet. 2019 Jun;181(2):230-244
pubmed: 31081998
Neurol Sci. 2018 Nov;39(11):1837-1845
pubmed: 30218397
Front Pediatr. 2018 Oct 23;6:316
pubmed: 30406066
J Hum Genet. 2015 Aug;60(8):435-42
pubmed: 25972034
Neuromuscul Disord. 2013 Jan;23(1):25-8
pubmed: 22939275
J Clin Invest. 1997 Nov 1;100(9):2204-10
pubmed: 9410897
Hum Mol Genet. 1995 Sep;4(9):1475-83
pubmed: 8541829
Hum Mutat. 2009 Sep;30(9):1329-39
pubmed: 19606495
Front Pharmacol. 2019 Jul 25;10:814
pubmed: 31404137
Anal Biochem. 2010 Nov 15;406(2):176-84
pubmed: 20670611
J Hum Genet. 2010 Jun;55(6):379-88
pubmed: 20485447
Hum Mutat. 2004 Jan;23(1):57-66
pubmed: 14695533
Hum Genet. 2019 Jul;138(7):771-785
pubmed: 31168774
J Hum Genet. 2014 Aug;59(8):454-64
pubmed: 25007885
Nat Biotechnol. 2014 Aug;32(8):706
pubmed: 25101726
Hum Genet. 2020 Feb;139(2):247-255
pubmed: 31919629
Nature. 2007 May 3;447(7140):87-91
pubmed: 17450125
Nucleic Acids Res. 2009 May;37(9):e67
pubmed: 19339519
Nat Rev Mol Cell Biol. 2012 Nov;13(11):700-12
pubmed: 23072888
Curr Opin Neurol. 2016 Oct;29(5):621-7
pubmed: 27454578
Am J Med Genet. 1980;7(1):27-34
pubmed: 7211951
Eur J Hum Genet. 2005 Dec;13(12):1254-60
pubmed: 16077730
Methods Mol Biol. 2018;1687:157-169
pubmed: 29067662
J Mol Diagn. 2005 Aug;7(3):317-26
pubmed: 16049303
Brain. 2011 Dec;134(Pt 12):3547-59
pubmed: 22102647
PLoS One. 2015 Aug 18;10(8):e0135189
pubmed: 26284620
Orphanet J Rare Dis. 2018 Jul 4;13(1):109
pubmed: 29973226
Hum Mutat. 2009 Jun;30(6):934-45
pubmed: 19367636
Acta Neuropathol Commun. 2014 Sep 11;2:100
pubmed: 25214167
Genomics. 1997 Oct 1;45(1):132-9
pubmed: 9339369