Tissue- and cell-specific whole-transcriptome meta-analysis from brain and retina reveals differential expression of dystrophin complexes and new dystrophin spliced isoforms.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
27 01 2023
27 01 2023
Historique:
received:
20
06
2022
revised:
13
09
2022
accepted:
14
09
2022
pubmed:
22
9
2022
medline:
7
2
2023
entrez:
21
9
2022
Statut:
ppublish
Résumé
The large DMD gene encodes a group of dystrophin proteins in brain and retina, produced from multiple promoters and alternative splicing events. Dystrophins are core components of different scaffolding complexes in distinct cell types. Their absence may thus alter several cellular pathways, which might explain the heterogeneous genotype-phenotype relationships underlying central comorbidities in Duchenne muscular dystrophy (DMD). However, the cell-specific expression of dystrophins and associated proteins (DAPs) is still largely unknown. The present study provides a first RNA-Seq-based reference showing tissue- and cell-specific differential expression of dystrophins, splice variants and DAPs in mouse brain and retina. We report that a cell type may express several dystrophin complexes, perhaps due to expression in separate cell subdomains and/or subpopulations, some of which with differential expression at different maturation stages. We also identified new splicing events in addition to the common exon-skipping events. These include a new exon within intron 51 (E51b) in frame with the flanking exons in retina, as well as inclusions of intronic sequences with stop codons leading to the presence of transcripts with elongated exons 40 and/or 41 (E40e, E41e) in both retina and brain. PCR validations revealed that the new exons may affect several dystrophins. Moreover, immunoblot experiments using a combination of specific antibodies and dystrophin-deficient mice unveiled that the transcripts with stop codons are translated into truncated proteins lacking their C-terminus, which we called N-Dp427 and N-Dp260. This study thus uncovers a range of new findings underlying the complex neurobiology of DMD.
Identifiants
pubmed: 36130212
pii: 6708360
doi: 10.1093/hmg/ddac236
pmc: PMC9896479
doi:
Substances chimiques
Dystrophin
0
Codon, Terminator
0
Protein Isoforms
0
Types de publication
Meta-Analysis
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
659-676Informations de copyright
© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Références
Sci Rep. 2022 Jan 26;12(1):1410
pubmed: 35082358
Invest Ophthalmol Vis Sci. 2017 Apr 1;58(4):1941-1953
pubmed: 28384715
Biochem Biophys Res Commun. 1997 Oct 29;239(3):895-9
pubmed: 9367866
Sci Rep. 2017 Jan 03;7:39094
pubmed: 28045018
Nucleic Acids Res. 1996 Sep 1;24(17):3439-52
pubmed: 8811101
Hum Mol Genet. 1993 May;2(5):521-4
pubmed: 8518789
Hum Mol Genet. 2012 May 15;21(10):2263-76
pubmed: 22343141
Biochem Biophys Res Commun. 1997 Sep 18;238(2):492-7
pubmed: 9299538
Nat Genet. 2001 Dec;29(4):447-52
pubmed: 11694879
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
J Neurosci Res. 2018 Feb;96(2):180-193
pubmed: 28509351
J Neurosci. 2014 Sep 3;34(36):11929-47
pubmed: 25186741
Hum Genet. 2017 Sep;136(9):1155-1172
pubmed: 28597072
Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3890-5
pubmed: 16505381
J Biomed Biotechnol. 2010;2010:849426
pubmed: 20625423
Hum Mutat. 2007 Feb;28(2):183-95
pubmed: 17041906
J Neuromuscul Dis. 2020;7(2):77-95
pubmed: 32176650
Trends Biochem Sci. 1996 Jan;21(1):11-13
pubmed: 8848831
Hum Genet. 2015 Sep;134(9):993-1001
pubmed: 26152642
Neurosci Res. 2005 Sep;53(1):25-33
pubmed: 15993965
Hum Genet. 2017 Sep;136(9):1043-1057
pubmed: 28391524
Hum Mol Genet. 2016 Sep 1;25(17):3647-3653
pubmed: 27378693
Biochem Biophys Res Commun. 2014 Sep 12;452(1):79-84
pubmed: 25152393
J Child Neurol. 2008 Feb;23(2):155-62
pubmed: 18056690
Mol Neurobiol. 2020 Mar;57(3):1748-1767
pubmed: 31836945
Nature. 1989 Apr 6;338(6215):509-11
pubmed: 2648158
J Hum Genet. 2007;52(7):607-617
pubmed: 17579806
Nat Genet. 2019 Apr;51(4):606-610
pubmed: 30742112
Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12413-8
pubmed: 9356463
Invest Ophthalmol Vis Sci. 2011 Oct 07;52(11):7901-8
pubmed: 21896869
Invest Ophthalmol Vis Sci. 2000 Jan;41(1):294-304
pubmed: 10634634
Dev Cell. 2016 Jun 20;37(6):520-32
pubmed: 27326930
PLoS One. 2020 Mar 11;15(3):e0230083
pubmed: 32160266
Genes (Basel). 2020 Oct 10;11(10):
pubmed: 33050418
Am J Hum Genet. 1991 Feb;48(2):295-304
pubmed: 1990838
J Hum Genet. 2015 Jun;60(6):327-33
pubmed: 25833469
PLoS One. 2008 Aug 10;4(8):e6574
pubmed: 19649270
Int J Mol Sci. 2020 Oct 21;21(20):
pubmed: 33096920
Trends Neurosci. 2012 Aug;35(8):487-96
pubmed: 22626542
J Comput Biol. 1997 Fall;4(3):311-23
pubmed: 9278062
Neuromuscul Disord. 2019 Dec;29(12):913-919
pubmed: 31706698
Sci Rep. 2017 Oct 3;7(1):12575
pubmed: 28974727
Hum Genet. 2022 Jan;141(1):31-47
pubmed: 34907472
Hum Genet. 1999 Jul-Aug;105(1-2):2-9
pubmed: 10480348
PLoS One. 2015 Sep 17;10(9):e0137328
pubmed: 26378780
Biochem Biophys Rep. 2019 Nov 10;20:100703
pubmed: 31737793
Nucleic Acids Res. 1992 Apr 11;20(7):1725-31
pubmed: 1579466
Hum Mol Genet. 1995 Sep;4(9):1475-83
pubmed: 8541829
Dev Med Child Neurol. 2016 Jan;58(1):77-84
pubmed: 26365034
Mol Neurobiol. 2018 Feb;55(2):1376-1386
pubmed: 28127699
Hum Mol Genet. 1994 Aug;3(8):1309-16
pubmed: 7987307
BMC Neurosci. 2017 Aug 14;18(1):63
pubmed: 28806929
Eur J Hum Genet. 2016 Apr;24(4):562-8
pubmed: 26081639
Hum Genet. 1996 Feb;97(2):232-9
pubmed: 8566960
Cancer Cell Int. 2017 May 23;17:58
pubmed: 28546788
J Cell Biol. 1999 Nov 1;147(3):645-58
pubmed: 10545507
Am J Hum Genet. 1992 Mar;50(3):508-14
pubmed: 1539591
Glia. 2022 Mar;70(3):466-490
pubmed: 34773297
Physiol Rev. 2016 Jan;96(1):253-305
pubmed: 26676145
Int J Mol Sci. 2020 May 18;21(10):
pubmed: 32443516
Neurosci Lett. 2020 Sep 25;736:135247
pubmed: 32668267
Glia. 2021 Apr;69(4):954-970
pubmed: 33247858
Glia. 2016 May;64(5):716-29
pubmed: 26711882
Biochem Biophys Res Commun. 1995 Oct 4;215(1):361-7
pubmed: 7575614
Nat Commun. 2015 May 28;6:7205
pubmed: 26018658
Biochem Biophys Res Commun. 2021 Jun 30;560:152-158
pubmed: 33989907
Hum Mol Genet. 1995 Mar;4(3):329-35
pubmed: 7795584
Genomics. 1997 Oct 1;45(1):132-9
pubmed: 9339369