Alternative splicing in multiple sclerosis and other autoimmune diseases

Figures & data

Figure 1 Alternative pre-mRNA splicing. (A) alternative use of 5′ splice sites; (B) alternative use of 3′ splice sites; (C) intron retention; (D) alternative use of a cassette exon; (E) alternative use of two mutually exclusive exons. For explanations, see text.

Figure 2 Schematic representation of IL7R pre-mRNA splicing. Genomic and pre-mRNA structure of the IL7R gene is shown (top), with SNPs selected for genotyping in reference 19, listed above. The MS-associated SNP, rs6897932, is highlighted. Alternative splicing of the IL7R pre-mRNA leads to the production of two isoforms: a membrane-bound (rIL7R, exon 6 included) or soluble (sIL7R, exon 6 skipped). The transmembrane isoform of the receptor consists of the extracellular (EX), transmembrane (TM) and cytoplasmic (CYTO) domains. Skipping of exon 6 leads to a translation reading frame shift and translation termination due to a premature stop codon. Adapted in part from reference 23.

Table 1 Alternatively spliced genes that are implicated in autoimmune diseases

Autoimmune disease	Alternatively spliced pre-mRNA	Consequence	Ref.
Multiple sclerosis	IL7R (skipping of exon 6)	more sIL7R produced	19, 22–24
	OAS1 (new 3′ splice site)	new isoforms	68
	KLC1 (SNP in intron 13)	?	74
	MBP	multiple isoforms	79–81
	MOG	multiple isoforms	82–84
	PLP (alternative 5′ splice sites)	two isoforms	85, 90
Myasthenia gravis	AChE	two isoforms	98, 99
	CTLA-4	different isoforms	100
Systemic lupus erythematosus	BANK1 (SNP at branch point)	isoform lacking exon 2	106
	LILRA2 (activation of cryptic 3′ splice site)	novel isoform lacking 3 amino acids	107
	TCRζ (skipping of exon 7; alternative splicing of 3′-UTR)	different isoforms	108–110
	IRF5 (alternative 5′ splice sites)	specific exon 1 used	114
	RasGRP1	aberrant splice variants	115
	CD72 (13-nucleotide repeats and 4 bp deletion in intron 8)	isoform lacking exon 8	116
	IL20R (alternatively spliced in the mouse model of SLE)	soluble receptor	117
	CR2 (SNPs)	decreased splicing efficiency of exon 11	118
Ulcerative colitis	PTPσ (skipping of exons 8, 9)	isoform lacking Ig-like domain	101
Scleroderma	IL4	truncated isoform	119, 120
Rheumatoid arthritis	IL6R	soluble receptor	111, 112
	TNFR2 (skipping of exons 7, 8)	novel soluble receptor	113
	Tenascin-C	increase in large isoform	121
	CD1d	soluble isoforms	122
	CD44	multiple splice variants	123–125
	Fibronectin	isoform containing EDA region	126
CD137	soluble receptor isoforms	127
Autoimmune inner ear disease	IL1R2	two isoforms
Type 1 diabetes	TAP2	two isoforms
	IA2	differential isoform expression
Kawasaki disease	ITPKC (SNP in intron 1 disrupts a poly-G run)	decreased splicing efficiency

Abbreviations: AChE, acetylcholinesterase; BANK1, B-cell scaffold protein with ankyrin repeats; CR2, complement receptor 2; EDA, extra domain A; IA2, insulinoma-associated tyrosine phosphatase-like protein; Ig-like, immunoglobulin-like; IL4, interleukin 4; IL1R2, interleukin-1 receptor type II; IL6R, interleukin 6 receptor; IL7Ra, interleukin 7 receptor a chain; IL20R, interleukin 20 receptor; IRF5, interferon regulatory factor 5; ITPKC, inositol 1,4,5-triphosphate 3-kinase C; KLC1, kinesin light-chain 1; LILRA2, leukocyte immunoglobulin-like receptor A2; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; OAS1, 2′,5′-oligoadenylate synthetase 1; PLP, proteolipid protein; PTPσ, protein-tyrosine phosphatase sigma; RasGRP1, Ras guanyl-nucleotide releasing protein 1; TCRζ, T-cell receptor σ chain; TAP2, transporter 2, ATP-binding cassette, subfamily B; TNFR2, receptor for tumor necrosis factor α2; 3′-UTR, 3′-untranslated region. A question mark (“?”) designates isoforms that have been predicted, but not shown, to arise from alternative splicing.

Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, et al. Interleukin 7 receptor a chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genetics 2007; 39:1083 - 1091

 PubMed Web of Science ®Google Scholar

Korte A, Köchling J, Badiali L, Eckert C, Andreae J, Geilen W, et al. Expression analysis and characterization of alternatively spliced transcripts of human IL7Rα chain encoding two truncated receptor proteins in relapsed childhood ALL. Cytokine 2000; 12:1597 - 1608

 PubMed Web of Science ®Google Scholar

Goodwin RG, Friend D, Ziegler SF, Jerzy R, Falk BA, Gimpel S, et al. Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily. Cell 1990; 60:941 - 951

 PubMed Web of Science ®Google Scholar

McKay FC, Swain LI, Schibeci SD, Rubio JP, Kilpatrick TJ, Heard RN, et al. Haplotypes of the interleukin7 receptor alpha gene are correlated with altered expression in whole blood cells in multiple sclerosis. Genes Immun 2008; 9:1 - 6

 PubMed Web of Science ®Google Scholar

Fedetz M, Matesanz F, Caro-Maldonado A, Fernandez O, Tamayo JA, Guerrero M, et al. OAS1 gene haplo-type confers susceptibility to multiple sclerosis. Tissue Antigens 2006; 68:446 - 449

 PubMed Web of Science ®Google Scholar

Szolnoki Z, Kondacs A, Mandi Y, Somogyvari F. A cytoskeleton motor protein genetic variant may exert a protective effect on the occurrence of multiple sclerosis: the janus face of the kinesin light-chain 1 56836CC genetic variant. Neuromol Med 2007; 9:335 - 339

 PubMed Web of Science ®Google Scholar

Shiryaev SA, Savinov AY, Cieplak P, Ratnikov BI, Motamedchaboki K, Smith JW, et al. Matrix metalloproteinase proteolysis of the myelin basic protein isoforms is a source of immunogenic peptides in auto-immune multiple sclerosis. PLoS ONE 2009; 4:4952

 PubMed Web of Science ®Google Scholar

Pribyl TM, Campagnoni C, Kampf K, Handley VS, Campagnoni AT. The major myelin protein genes are expressed in the human thymus. J Neurosci Res 1996; 45:812 - 819

 PubMed Web of Science ®Google Scholar

Delarasse C, Della Gaspera B, Lu CW, Lachapelle F, Gelot A, Rodriguez D, et al. Complex alternative splicing of the myelin oligodendrocyte glycoprotein gene is unique to human and non-human primates. J Neurochem 2006; 98:1707 - 1717

 PubMed Web of Science ®Google Scholar

Allamargot C, Gardinier MV. Alternative isoforms of myelin/oligodendrocyte glycoprotein with variable cytoplasmic domains are expressed in human brain. J Neurochem 2007; 101:298 - 312

 PubMed Web of Science ®Google Scholar

Pribyl TM, Campagnoni CW, Kampf K, Kashima T, Handley VW, McMahon J, Campagnoni AT. Expression of the myelin proteolipid protein gene in the human fetal thymus. J Neuroimmunol 1996; 67:125 - 130

 PubMed Web of Science ®Google Scholar

Klein L, Klugmann M, Nave K-A, Tuohy VK, Kyewski B. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat Med 2000; 6:56 - 61

 PubMed Web of Science ®Google Scholar

Jurica MS. Detailed close-ups and the big picture of spliceosomes. Curr Opin Struct Biol 2008; 18:315 - 320

 PubMed Web of Science ®Google Scholar

Sussman JD, Argov Z, McKee D, Hazum E, Brawer S, Soreq H. Antisense treatment for Myasthenia gravis. Experience with Monarsen. Ann NY Acad Sci 2008; 1132:283 - 290

 PubMed Web of Science ®Google Scholar

Gu M, Kakoulidou M, Giscombe R, Pirskanen R, Lefvert AK, Klareskog L, et al. Identification of CTLA-4 isoforms produced by alternative splicing and their association with myasthenia gravis. Clinical Immunol 2008; 128:374 - 381

 PubMed Web of Science ®Google Scholar

Kozyrev SV, Abelson A-K, Wojcik J, Zaghlool A, Prasad Linga Reddy MV, Sanchez E, et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet 2008; 40:211 - 216

 PubMed Web of Science ®Google Scholar

Mamegano K, Kuroki K, Miyashita R, Kusaoi M, Kobayashi S, Matsuta K, et al. Association of LILRA2 (ILT1, LIR7) splice site polymorphism with systemic lupus erythematosus and microscopic polyangiitis. Genes Immun 2008; 9:214 - 223

 PubMed Web of Science ®Google Scholar

Tsuzaka K, Setoyama Y, Yoshimoto K, Shiraishi K, Suzuki K, Abe T, et al. A splice variant of the TCRζ mRNA lacking exon 7 leads to the downregulation of TCRζ, the TCR/CD3 complex, and IL-2 production in systemic lupus erythematosus T cells. J Immunol 2005; 174:3518 - 3525

 PubMed Web of Science ®Google Scholar

Tsuzaka K, Nozaki K, Kumazawa C, Shiraishi K, Setoyama Y, Yoshimoto K, et al. TCRζ mRNA splice variant forms observed in the peripheral blood T cells from systemic lupus erythematosus patients. Springer Semin Immun 2006; 28:185 - 193

 PubMed Web of Science ®Google Scholar

Yasuda S, Stevens RL, Terada T, Takeda M, Hashimoto T, Fukae J, et al. Defective expression of Ras Guanyl Nucleotide-Releasing protein 1 in a subset of patients with systemic lupus erythematosus. J Immunol 2007; 179:4890 - 4900

 PubMed Web of Science ®Google Scholar

Wei C-C, Chang M-S. A novel transcript of mouse interleukin-20 receptor acts on glomerular mesangial cells as an aggravating factor in lupus nephritis. Genes and Immunity 2008; 9:668 - 679

 PubMed Web of Science ®Google Scholar

Douglas KB, Windels DC, Zhao, Gadeliya AV, Wu H, Kaufmann KM, et al. Complement receptor 2 polymorphisms associated with systemic lupus erythematosus modulate alternative splicing. Genes Immun 2009; 10:457 - 469

 PubMed Web of Science ®Google Scholar

Muise AM, Walters T, Wine E, Griffiths AM, Turner D, Duerr RH, et al. Protein-tyrosine phosphatase sigma is associated with ulcerative colitis. Curr Biol 2007; 17:1212 - 1218

 PubMedGoogle Scholar

Sakkas LI, Tourtellotte C, Berney S, Myers AR, Platsoucas CD. Increased levels of alternatively spliced interleukin 4 (IL-4δ2) transcripts in peripheral blood mononuclear cells from patients with systemic sclerosis. Clin Diagn Lab Immunol 1999; 6:660 - 664

 PubMedGoogle Scholar

Atamas SP, White B. Interleukin 4 in systemic sclerosis: not just an increase. Clin Diagn Lab Immunol 1999; 6:658 - 659

 PubMedGoogle Scholar

Rose-John S, Waetzig GH, Scheller J, Grotzinger J, Seegert D. The IL-6/sIL-6R complex as a novel target for therapeutic approaches. Expert Opin Ther Targets 2007; 11:613 - 624

 PubMed Web of Science ®Google Scholar

Kotake S, Sato K, Kim KJ, Takajashi N, Udagawa N, Nakamura I, et al. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 1996; 11:88 - 95

 PubMed Web of Science ®Google Scholar

Lainez B, Fernandez-Reeal JM, Romero X, Esplugues E, Canete JD, Ricart W, et al. Identification and characterization of a novel spliced variant that encodes human soluble tumor necrosis factor receptor 2. Int Immunol 2004; 16:169 - 177

 PubMed Web of Science ®Google Scholar

Hasegawa M, Nakoshi Y, Muraki M, Sudo A, Kinoshita N, Yoshida T, et al. Expression of large tenascin-C splice variants in synovial fluid of patients with rheumatoid arthritis. J Orthop Res 2007; 25:563 - 568

 PubMed Web of Science ®Google Scholar

Kojo S, Tsutsumi A, Goto D, Sumida T. Low expression levels of soluble CD1d gene in patients with rheumatoid arthritis. J Rheumatol 2003; 30:2524 - 2528

 PubMed Web of Science ®Google Scholar

Croft DR, Dall P, Davies D, Jackson DG, McIntyre P, Kramer IM. Complex CD44 splicing combinations in synovial fibroblasts from arthritic joints. Eur J Immunol 1997; 27:1680 - 1684

 PubMed Web of Science ®Google Scholar

Naor D, Nedvetzki S. CD44 in rheumatoid arthritis. Arthritis Res Ther 2003; 5:105 - 115

 PubMed Web of Science ®Google Scholar

Shiozawa K, Hino K, Shiozawa S. Alternatively spliced EDA-containing fibronectin in synovial fluid as a predictor of rheumatoid joint destruction. Rheumatology 2001; 40:739 - 742

 PubMed Web of Science ®Google Scholar

Michel J, Langstein J, Hofstadter F, Schwarz H. A soluble form of CD137 (ILA/4-1BB), a member of the TNF receptor family, is released by activated lymphocytes and is detectable in sera of patients with rheumatoid arthritis. Eur J Immunol 1998; 28:290 - 295

 PubMed Web of Science ®Google Scholar