title: Interplay between DMD point mutations and splicing signals in Dystrophinopathy phenotypes.
abstract: DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered a key modifier of disease severity. Several exonic mutations have been shown to induce exon-skipping, while splice site mutations result in exon-skipping or activation of cryptic splice sites. However, factors determining the splicing pathway are still unclear. Point mutations provide valuable information regarding the regulation of pre-mRNA splicing and elements defining exon identity in the DMD gene. Here we provide a comprehensive analysis of 98 point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression. Aberrant splicing was found in 27 mutations due to alteration of splice sites or splicing regulatory elements. Bioinformatics analysis was performed to test the ability of the available algorithms to predict consequences on mRNA and to investigate the major factors that determine the splicing pathway in mutations affecting splicing signals. Our findings suggest that the splicing pathway is highly dependent on the interplay between splice site strength and density of regulatory elements.
authors.affiliation: Servei de Genètica, Hospital de la Santa Creu i Sant Pau and CIBERER U705, Barcelona, Spain ; Universitat de Barcelona (UB), Barcelona, Spain.
authors.forename: Jonàs
authors.initials: J
authors.lastname: Juan-Mateu
authors.forename: Lidia
authors.initials: L
authors.lastname: González-Quereda
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Rodríguez
authors.forename: Edgard
authors.initials: E
authors.lastname: Verdura
authors.forename: Kira
authors.initials: K
authors.lastname: Lázaro
authors.forename: Cristina
authors.initials: C
authors.lastname: Jou
authors.forename: Andrés
authors.initials: A
authors.lastname: Nascimento
authors.forename: Cecilia
authors.initials: C
authors.lastname: Jiménez-Mallebrera
authors.forename: Jaume
authors.initials: J
authors.lastname: Colomer
authors.forename: Soledad
authors.initials: S
authors.lastname: Monges
authors.forename: Fabiana
authors.initials: F
authors.lastname: Lubieniecki
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Foncuberta
authors.forename: Samuel Ignacio
authors.initials: SI
authors.lastname: Pascual-Pascual
authors.forename: Jesús
authors.initials: J
authors.lastname: Molano
authors.forename: Montserrat
authors.initials: M
authors.lastname: Baiget
authors.forename: Pia
authors.initials: P
authors.lastname: Gallano
mesh_terms: D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D005838:Genotype; D006801:Humans; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D010641:Phenotype; D017354:Point Mutation; D022821:RNA Splice Sites; D012326:RNA Splicing
chemical_list: D016189:Dystrophin; D022821:RNA Splice Sites
references.citation: RNA. 2007 Oct;13(10):1609-24
references.pmid: 17684229
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W187-90
references.pmid: 15215377
references.citation: Nat Genet. 2002 Apr;30(4):377-84
references.pmid: 11925564
references.citation: Genomics. 1988 Jan;2(1):90-5
references.pmid: 3384440
references.citation: RNA. 2004 May;10(5):757-65
references.pmid: 15100430
references.citation: Hum Mutat. 2011 Mar;32(3):299-308
references.pmid: 21972111
references.citation: Cell. 1987 Dec 24;51(6):919-28
references.pmid: 3319190
references.citation: J Clin Invest. 1997 Nov 1;100(9):2204-10
references.pmid: 9410897
references.citation: J Hum Genet. 2010 Jun;55(6):379-88
references.pmid: 20485447
references.citation: Nat Methods. 2010 Apr;7(4):248-9
references.pmid: 20354512
references.citation: Eur J Hum Genet. 2005 Dec;13(12):1254-60
references.pmid: 16077730
references.citation: Am J Hum Genet. 2003 Apr;72(4):931-9
references.pmid: 12632325
references.citation: Nucleic Acids Res. 2003 Jan 1;31(1):334-41
references.pmid: 12520017
references.citation: Nucleic Acids Res. 1987 Sep 11;15(17):7155-74
references.pmid: 3658675
references.citation: Cell. 1988 Apr 22;53(2):219-28
references.pmid: 3282674
references.citation: Hum Mutat. 2007 Feb;28(2):183-95
references.pmid: 17041906
references.citation: J Comput Biol. 2004;11(2-3):377-94
references.pmid: 15285897
references.citation: N Engl J Med. 2007 Dec 27;357(26):2677-86
references.pmid: 18160687
references.citation: Clin Genet. 2012 Dec;82(6):574-8
references.pmid: 22092019
references.citation: Nature. 1990 Jan 11;343(6254):180-2
references.pmid: 2404210
references.citation: Cell. 2004 Dec 17;119(6):831-45
references.pmid: 15607979
references.citation: Am J Hum Genet. 1995 Jan;56(1):158-66
references.pmid: 7825572
references.citation: Genome Res. 2005 Jun;15(6):768-79
references.pmid: 15930489
references.citation: Hum Mutat. 1998;Suppl 1:S137-8
references.pmid: 9452067
references.citation: Ann Hum Genet. 2008 Nov;72(Pt 6):717-24
references.pmid: 18652600
references.citation: J Med Genet. 2006 Dec;43(12):924-30
references.pmid: 16738009
references.citation: Muscle Nerve. 2006 Aug;34(2):135-44
references.pmid: 16770791
references.citation: Neuromuscul Disord. 2003 May;13(4):317-21
references.pmid: 12868501
references.citation: FEBS Lett. 2006 Aug 7;580(18):4449-56
references.pmid: 16870183
references.citation: Neuromuscul Disord. 2001 Mar;11(2):133-8
references.pmid: 11257468
references.citation: Hum Genet. 2001 Oct;109(4):402-7
references.pmid: 11702221
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3568-71
references.pmid: 12824367
references.citation: Hum Mutat. 2009 Apr;30(4):633-40
references.pmid: 19206170
references.citation: Eur J Hum Genet. 2000 Oct;8(10):793-6
references.pmid: 11039581
references.citation: Nucleic Acids Res. 2007;35(11):3823-35
references.pmid: 17526529
references.citation: Nucleic Acids Res. 2006 Jul 19;34(12):3494-510
references.pmid: 16855287
references.citation: J Med Genet. 2009 Aug;46(8):542-7
references.pmid: 19001018
references.citation: Hum Mutat. 2007 Feb;28(2):150-8
references.pmid: 17001642
references.citation: Hum Mutat. 1999;14(5):359-68
references.pmid: 10533061
references.citation: Am J Hum Genet. 1991 Jul;49(1):54-67
references.pmid: 2063877
references.citation: J Comput Biol. 1997 Fall;4(3):311-23
references.pmid: 9278062
references.citation: Nucleic Acids Res. 2004 Mar 19;32(5):1783-91
references.pmid: 15034146
references.citation: Hum Mol Genet. 2006 Mar 15;15(6):999-1013
references.pmid: 16461336
references.citation: Genes Dev. 2004 Jun 1;18(11):1241-50
references.pmid: 15145827
references.citation: Nucleic Acids Res. 2009 May;37(9):e67
references.pmid: 19339519
references.citation: J Biol Chem. 2003 Apr 18;278(16):13591-4
references.pmid: 12556452
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5797-802
references.pmid: 18391195
references.citation: Hum Mol Genet. 2003 May 15;12(10):1111-20
references.pmid: 12719375
references.citation: Am J Med Genet A. 2009 Jul;149A(7):1499-503
references.pmid: 19530190
references.citation: Orphanet J Rare Dis. 2012 Oct 23;7:82
references.pmid: 23092449
references.citation: Hum Mutat. 2004 Dec;24(6):491-501
references.pmid: 15523642
references.citation: Neuromuscul Disord. 2010 Feb;20(2):102-10
references.pmid: 20079639
references.citation: Hum Mutat. 2009 Jun;30(6):934-45
references.pmid: 19367636
references.citation: Nucleic Acids Res. 2003 Nov 1;31(21):6321-33
references.pmid: 14576320
references.citation: Nat Protoc. 2009;4(7):1073-81
references.pmid: 19561590
references.citation: Hum Mol Genet. 2006 Aug 15;15(16):2490-508
references.pmid: 16825284