title: Investigation of splicing changes and post-translational processing of LMNA in sporadic inclusion body myositis.
abstract: Some features of sporadic inclusion body myositis (s-IBM) suggest that there is acceleration of the normal ageing process in muscle tissue. LMNA encodes the nuclear lamina proteins lamin A/C through alternative splicing, and aberrant splicing of exon 11 leads to the premature ageing disease, Hutchinson-Gilford progeria syndrome. Progerin, the pathogenic isoform expressed in HGPS tissues, has also been detected at low levels in tissues of normal individuals with aging. We therefore investigated the alternative splicing of LMNA gene transcripts, and the post-translational processing of prelamin A, in s-IBM and control muscle samples. Age-related low level expression of the progerin transcript was detected in both s-IBM and control muscles, but was not increased in s-IBM and there was no increase in progerin protein or demonstrable accumulation of intermediate prelamin isoforms in the s-IBM muscles. However, an age-related shift in the balance of splicing towards lamin A-related transcripts, which was present in normal muscles, was not found in s-IBM. Our findings indicate that while there are changes in the patterns of LMNA splicing in s-IBM muscle which are probably secondary to the underlying pathological process, it is unlikely that aberrant splicing of exon 11 or defective post-translational processing of prelamin A are involved in the pathogenesis of the disease.
authors.affiliation: Centre for Neuromuscular and Neurological Disorders, Australian Neuro-Muscular Research Institute, University of Western Australia Perth, Australia ; Laboratory of Neuromuscular Disorders, Department of Neurology, Qilu Hospital, Shandong University Jinan, China.
authors.forename: Yue-Bei
authors.initials: YB
authors.lastname: Luo
authors.forename: Chalermchai
authors.initials: C
authors.lastname: Mitrpant
authors.forename: Russell
authors.initials: R
authors.lastname: Johnsen
authors.forename: Vicki
authors.initials: V
authors.lastname: Fabian
authors.forename: Merrilee
authors.initials: M
authors.lastname: Needham
authors.forename: Sue
authors.initials: S
authors.lastname: Fletcher
authors.forename: Steve D
authors.initials: SD
authors.lastname: Wilton
authors.forename: Frank L
authors.initials: FL
authors.lastname: Mastaglia
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000378:metabolism; D017398:Alternative Splicing; D016022:Case-Control Studies; D002478:Cells, Cultured; D005091:Exons; D005260:Female; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D018979:Myositis, Inclusion Body / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011371:Progeria / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D012307:Risk Factors
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D012313:RNA
keywords: Inclusion body myositis; LMNA; lamin A/C; muscle; prelamin A; progerin
references.citation: Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3000-4
references.pmid: 1557405
references.citation: Lancet Neurol. 2007 Jul;6(7):620-31
references.pmid: 17582362
references.citation: Hum Mol Genet. 2005 Jun 1;14(11):1503-13
references.pmid: 15843403
references.citation: Exp Cell Res. 2008 Dec 10;314(20):3628-37
references.pmid: 18951892
references.citation: J Neuropathol Exp Neurol. 1998 May;57(5):396-403
references.pmid: 9596410
references.citation: Neurobiol Aging. 2010 Jul;31(7):1205-14
references.pmid: 18823681
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10291-6
references.pmid: 16014412
references.citation: Hum Mutat. 2007 Sep;28(9):882-9
references.pmid: 17469202
references.citation: Neurology. 1999 Nov 10;53(8):1671-6
references.pmid: 10563611
references.citation: Physiol Genomics. 2005 Oct 17;23(2):150-8
references.pmid: 16046620
references.citation: Acta Neuropathol. 1996;91(5):530-6
references.pmid: 8740235
references.citation: Clin Neuropathol. 2008 Nov-Dec;27(6):424-9
references.pmid: 19130741
references.citation: J Cell Biochem. 2007 Dec 1;102(5):1149-59
references.pmid: 17654502
references.citation: Histochem Cell Biol. 1997 Jun;107(6):505-17
references.pmid: 9243284
references.citation: Annu Rev Genomics Hum Genet. 2009;10:153-74
references.pmid: 19453251
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16690-5
references.pmid: 16269543
references.citation: J Neurol Neurosurg Psychiatry. 2004 Jun;75(6):917-20
references.pmid: 15146016
references.citation: Mol Ther. 2007 Jan;15(1):157-66
references.pmid: 17164787
references.citation: Eur J Hum Genet. 2009 Jul;17(7):928-37
references.pmid: 19172989
references.citation: PLoS One. 2007 Dec 05;2(12):e1269
references.pmid: 18060063
references.citation: Neuromuscul Disord. 2002 Jun;12(5):484-93
references.pmid: 12031622
references.citation: Nature. 2003 May 15;423(6937):293-8
references.pmid: 12714972
references.citation: Nat Med. 2005 Jul;11(7):780-5
references.pmid: 15980864
references.citation: Aging Cell. 2004 Aug;3(4):235-43
references.pmid: 15268757
references.citation: Hum Mol Genet. 2004 Oct 15;13(20):2493-503
references.pmid: 15317753
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):4949-54
references.pmid: 17360355
references.citation: Physiol Rev. 2006 Jul;86(3):967-1008
references.pmid: 16816143
references.citation: Neuromuscul Disord. 2013 Jan;23(1):75-83
references.pmid: 23058947
references.citation: Brain. 1993 Apr;116 ( Pt 2):325-36
references.pmid: 8384916
references.citation: J Clin Neurosci. 2008 Dec;15(12):1350-3
references.pmid: 18815046
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15902-7
references.pmid: 18838683
references.citation: Muscle Nerve. 2006 Oct;34(4):406-16
references.pmid: 16823856
references.citation: Science. 2006 May 19;312(5776):1059-63
references.pmid: 16645051
references.citation: Cell Death Differ. 2011 Aug;18(8):1305-15
references.pmid: 21311568
references.citation: J Biol Chem. 2006 Dec 29;281(52):39741-5
references.pmid: 17090536
references.citation: Am J Pathol. 1994 May;144(5):874-82
references.pmid: 8178939
references.citation: Exp Cell Res. 2008 Feb 1;314(3):453-62
references.pmid: 18093584
references.citation: Hum Mol Genet. 2010 Jul 1;19(13):2682-94
references.pmid: 20421363
references.citation: Mol Biol Cell. 2008 Dec;19(12):5398-408
references.pmid: 18923140
references.citation: J Lipid Res. 2005 Dec;46(12):2531-58
references.pmid: 16207929