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Is the T-G-CT-G SNRNP70 Haplotype Another Proof That Mixed Connective

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Is the T-G-CT-G SNRNP70 Haplotype Another Proof That Mixed Connective Is the T-G-CT-G SNRNP70 haplotype another proof that mixed connective tissue disease is distinct from systemic lupus erythematosus and systemic sclerosis? A novel gene variant in SNRNP70 gene A. Paradowska-Gorycka1, A. Wajda1, I. Stolarek2, A. Felis-Giemza3, M. Walczyk3, J. Nałecz-Janik3, M. Olesińska3 1Department of Molecular Biology, ABSTRACT Introduction National Institute of Geriatrics, Objective. U1-70K, encoded by the In 1990, Spritz et al. (1) introduced the Rheumatology and Rehabilitation, SNRNP70 gene, is a key early immu- sequence of SNRNP70 gene, which is Warsaw; nogen in connective tissue disease. The mapped on chromosome 19q13.33. SN- 2Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan; aim of the study was the genetic analy- RNP70 gene encoding the human U1- 3Department of Connective Tissue sis of the SNRNP70 gene in mixed con- 70K protein belonging to the U1 small Diseases, National Institute of Geriatrics, nective tissue disease (MCTD), sys- nuclear ribonucleoprotein (snRNP also Rheumatology and Rehabilitation, temic lupus erythematosus (SLE) and known as U1-RNP) complex, which is Warsaw, Poland. systemic sclerosis (SSc) patients. a key component of the spliceosome Agnieszka Paradowska-Gorycka, PhD Methods. SNRNP70 genetic vari- (2-4). U1-70K protein contains an N- Anna Wajda, PhD ants were detected using 3730 DNA terminal domain, an 80 amino acid Ireneusz Stolarek, PhD Analyzer. SNRNP70 rs560811128 G/A RNA binding domain (RBP) with two Anna Felis-Giemza, PhD (c.476-252 G/A), rs78616533delCT characteristics RNA recognition motifs Marcela Walczyk, MD Jolanta Nałecz-Janik, PhD (c.475+130_475+131delCT) and (RRMs) and a C-terminal domain with Marzena Olesińska, MD, PhD rs117167710 T/C (c.393+326 T/C) two Arg-rich domains. U1-70K protein Please address correspondence to: variants were genotyped using the tech- through RNP-80 motif directly binds Dr Agnieszka Paradowska-Gorycka, nique of sequence-specific hybridisa- to stem-loop I of U1-RNA as an indi- Department of Molecular Biology, tion probe binding assays. SNRNP70 vidual molecule (5-9). National Institute of Geriatrics, 393_47 G/A mutation was detected us- The U1-70K protein and U1-RNA in- Rheumatology and Rehabilitation, ing TaqMan SNP genotyping assay. volved immune cells, such as B and T Spartańska 1, Results. We found one novel cells, as well as their receptors in com- 02-637 Warszawa, Poland. c.393+47G>A and three, c.476-252 E-mail: [email protected]; plex interactions leading to the produc- agnieszka.paradowska-gorycka@ G/A, c.475+130_475+131delCT and tion of autoantibodies, inflammation spartanska.pl c.393+326 T/C, previously recorded and tissue damage (8, 10). Moreover, Received on April 3, 2019; accepted in variants. The present study revealed protein components of the U1-snRNP revised form on May 27, 2019. that T-G-CT-G haplotype demon- complex are targeted by autoantibodies Clin Exp Rheumatol 2019; 37 (Suppl. 119): strated significantly higher frequen- present in patients with systemic lupus S32-S40. cies in MCTD patients than in SLE erythematosus (SLE), systemic sclero- © Copyright CLINICAL AND and SSc patients. In MCTD patients sis (SSc) and mixed connective tissue EXPERIMENTAL RHEUMATOLOGY 2019. c.475+130_475+131delCT distribu- disease (MCTD) (11-14). Anti-U1- tion of genotype was gender-dependent snRNP antibodies are observed in 30– Key words: SNRNP70, anti-U1-70K, and showed association with thrombo-/ 35% of SLE patients, 2-14% of SSc pa- MCTD, phenotype, genetics leukocytopenia. Mutation at position tients and in nearly all, if not all, MCTD c.476-252G>A was predicted to pos- patients (8, 11, 12, 15). Antibodies sibly have an impact on splicing of the against U1-70K develop as first, in the SNRNP70 transcript and it was present early immune response, and participate only in one MCTD patient. in the development of other antibodies. Conclusion. Our results demonstrated They are detected in 75–90% of MCTD that the T-G-CT-G SNRNP70 haplo- patients but in contrast, they have de- type is another proof that MCTD may tected only in 20–50% of SLE patients be distinct from SLE and SSc. The novel whose sera is anti-RNP positive (8, 12, Funding: this work was supported by c.476-252G>A mutation in SNRNP70 16, 17). A prerequisite for the diagnosis a grant from the Polpharma Scientific gene created a new acceptor splice site of MCTD is the presence of anti-U1- Foundation. and may potentially alert of splicing of RNP antibodies. In patients with high Competing interests: none declared. the SNRNP70 transcript. titres of these antibodies who do not S-32 Clinical and Experimental Rheumatology 2019 SNRNP70 gene in MCTD, SLE and SSc. / A. Paradowska-Gorycka et al. meet the criteria for MCTD diagnosis Table I. Patients’ characteristics. or any other connective tissue disease, Characteristics MCTD SLE SSc MCTD usually develops within 2 years. n=83 n=97 n=71 U1-70K is a major early immunogen mean values ± SD mean values ± SD mean values ± SD might be important for triggering of the immune response to U1-snRNP com- Age [years] 42.71 ± 13.40 40.58 ± 12.73 55.06 ± 13.47 Disease duration [years] 9.75 ± 8.52 3.85 ± 5.97 4.99 ± 7.50 plex (13, 16, 17). Gender 67 (81%) female 90 (93%) female 53 (75%) female However, the precise role of the U1- 16 (19%) male 7 (7%) male 18 (25%) male 70K protein and especially SNRNP70 Damage index MCTD-DI SLICC gene in the pathogenesis of MCTD, [median range (min-max)] 5 (0-68) 4 (0-17) 2 (0-15) SLE and/or SSc is unknown. To verify Activity index MCTD-AI SELENA_SLEDAI whether genetic variation located in [median range (min-max)] 9.4 (0-32) 4 (0-17) 0.5 (0-9) the SNRNP70 gene may be a factor ESR [mm/h] 27.58 ± 23 32.62 ± 26.89 19.37 ± 16.54 explaining phenotype or characteris- CRP [mg/L] 11.63 ± 14.80 25.7 ± 57.62 8.28 ± 11.21 tics above connective tissue diseases n** (%) (CTD), we used gene sequencing for anti-dsDNA 12 (14%) 58 (60) 1 (1%) anti-SSA Ro60 8 (10%) 37 (38%)-SSA 1 (1%) detection of all polymorphisms/muta- Ro52 23 (28%) 1 (1%) tion located in this gene. anti-SSB 1 (1%) 12 (12%) 0 (0%) anti-SM SmB 27 (33%) 14 (14%) 0 (0%) Materials and methods SmD 5 (6%) 0 (0%) anti-Rib 3 (4%) 10 (10%) 0 (0%) Study populations anti-Jo 2 (2%) 0 (0%) 0 (0%) A total of 504 individuals were selected anti-histon 12 (14%) 22 (23%) 1 (1%) to participate in this study. Peripheral anti-Scl-70 2 (2%) 1 (1%) 5 (7%) blood samples from 135 MCTD pa- anti-U1-RNP 82 (99%) 14 (14%) 0 anti-70K 60 (72%) - - tients, 135 SLE patients, 81 SSc pa- anti-A 68 (82%) - - tients, and 153 healthy subjects were anti-C 64 (77%) - - obtained. All patients were recruited Sjögren 18 (22%) 16 (16%) - from the Department of Connective Tis- Raynaud’s phenomenon 80 (96%) - 47 (66%) Facial erythema 36 (43%) 44 (45%) - sue Diseases of the National Institute of arthritis 78 (94%) 62 (64%) 24 (34%) Geriatrics, Rheumatology and Rehabili- Pulmonary fibrosis 28 (34%) 5 (5%) 21 (30%) tation. Healthy control participants were Leukopenia/trombocytopenia 51 (61%) 52 (50%) - recruited from the Regional Center for MCTD: mixed connective tissue disease; SLE: systemic lupus erythematosus; SSc: systemic sclero- Blood Donation and Blood Treatment in sis; SD: standard deviation; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; MCTD- Warsaw. Healthy subjects did not have -DI: MCTD damage index; SLICC: Systemic Lupus International Collaborating Clinics; MCTD-AI: a history of autoimmune and/or inflam- MCTD activity index; SELENA-SLEDAI: Systemic Lupus Erythematosus Disease Activity Index. matory disease at the time of sampling. MCTD patients, SLE patients, SSc Collaborating Clinics/American Col- tigation was approved by the Research patients, and healthy subjects were of lege of Rheumatology (SLICC/ACR) Ethics Committee of the National In- Caucasian origin. Characteristics of all Damage Index (SLICC/ACR DI). Dam- stitute of Geriatrics, Rheumatology and participants were summarised in Ta- age most commonly affected skin, mus- Rehabilitation in Warsaw. All partici- ble I, where we presented only those culoskeletal and cardiovascular systems pants, patients, and healthy donors gave clinical parameters which are shared and lungs. Autoantibodies to Sm, Ro, informed written consent and research by the three diseases. Objective meth- La, RibP, PCNA, CENPB, Scl-70, Jo-1, was conducted in accordance with the ods were constructed based on the tools His, dsDNA were measured in sera us- Declaration of Helsinki. employed in SLE; an MCTD activity ing DOT-blot tests (recomLine ANA/ index (MCTD-AI) was modeled on the ENA, Mikrogen Diagnostik, Neuried, Mixed connective tissue disease Systemic Lupus Erythematosus Disease Germany). The identification of antinu- patients Activity Index (SLEDAI) score. The clear antibodies (ANA) was performed MCTD patients met Alarcon-Segovia most common symptoms of the active by indirect immunofluorescence (IF) and Villarreal classification criteria, disease were: decreased number of leu- on Hep2 cell lines (Euroimmun Pol- which were chosen due to their very kocytes and/or platelets, swelling of the ska, Wroclaw, Poland), with median a high specificity for MCTD. Patients hands, increased of erythrocyte sedi- titre of 1:5,840 (range 1:80 – 1:40,960). with MCTD, who met the classification mentation rate (ESR) and/or C-reactive The presence of anti-U1-RNP was de- criteria for two connective tissue diseas- protein (CRP) levels, hypergamma- termined by electrochemiluminescence es at the same time were excluded from globulinaemia and skin rashes. MCTD (ECLIA) using streptavidin-coated par- the study.
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