Abstract：
BACKGROUND: Collagen type XI alpha 2 chain is a component of type XI collagen and is expressed in various tissues including articular cartilage and tectorial membrane of the cochlea. Variants in the COL11A2 gene, which encodes collagen type XI alpha 2 chain, has been reported to cause hearing loss and has been associated with osteoarthritis and ossification of the posterior longitudinal ligament of the spine. Despite the importance of type XI collagen in the joints, association of rheumatoid arthritis (RA) with COL11A2 has not been reported.
METHODS: The patient is a 60-year-old female, born to Japanese parents of no known consanguinity. She had progressive hearing loss since childhood. Her father also had progressive hearing loss before middle age. She developed joint pain in the knees and the hips in her forties. When she was 56, she developed polyarthritis. Rheumatoid factor and anti-CCP antibodies were positive.
METHODS: She was diagnosed with osteoarthritis and RA. Whole exome analysis detected 2 rare variants, c.4201C>T, p.(Arg1401Trp) and c4265C>T, p.(Pro1422Leu), in the COL11A2 gene (NM_080680.2). Whole genome analysis with a long insert size confirmed 2 variants that are in trans.
RESULTS: She received a cochlear implant, which improved her hearing. She was treated with methotrexate, golimumab, tocilizumab, and upadacitinib with partial responses for her RA.
CONCLUSIONS: We herein report a patient with RA with compound heterozygous variants in the COL11A2 gene. Autoantibodies against type XI collagen are detected in the sera of patients with RA, suggesting the possibility that type XI collagen may be involved in the pathogenesis of RA as an autoantigen. The hearing loss and osteoarthritis in this patient may be due to the compound heterozygous variants in the COL11A2 gene, and the conformational changes induced by the variants may have changed the immunogenicity of type XI collagen, leading to the development of RA.
METHODS: The patient is a 60-year-old female, born to Japanese parents of no known consanguinity. She had progressive hearing loss since childhood. Her father also had progressive hearing loss before middle age. She developed joint pain in the knees and the hips in her forties. When she was 56, she developed polyarthritis. Rheumatoid factor and anti-CCP antibodies were positive.
METHODS: She was diagnosed with osteoarthritis and RA. Whole exome analysis detected 2 rare variants, c.4201C>T, p.(Arg1401Trp) and c4265C>T, p.(Pro1422Leu), in the COL11A2 gene (NM_080680.2). Whole genome analysis with a long insert size confirmed 2 variants that are in trans.
RESULTS: She received a cochlear implant, which improved her hearing. She was treated with methotrexate, golimumab, tocilizumab, and upadacitinib with partial responses for her RA.
CONCLUSIONS: We herein report a patient with RA with compound heterozygous variants in the COL11A2 gene. Autoantibodies against type XI collagen are detected in the sera of patients with RA, suggesting the possibility that type XI collagen may be involved in the pathogenesis of RA as an autoantigen. The hearing loss and osteoarthritis in this patient may be due to the compound heterozygous variants in the COL11A2 gene, and the conformational changes induced by the variants may have changed the immunogenicity of type XI collagen, leading to the development of RA.
摘要：
背景：XI型胶原α2链是XI型胶原的组成部分，在包括关节软骨和耳蜗膜在内的各种组织中表达。COL11A2基因的变异，编码XI型胶原蛋白α2链，据报道会导致听力损失，并与骨关节炎和脊柱后纵韧带骨化有关。尽管XI型胶原蛋白在关节中的重要性，类风湿关节炎（RA）与COL11A2的相关性尚未报道。
方法：患者是一名60岁的女性，出生于没有血缘关系的日本父母。她从小就有进行性听力损失。她的父亲在中年之前也有进行性听力损失。她四十多岁时膝盖和臀部出现关节痛。56岁时，她患上了多关节炎。类风湿因子和抗CCP抗体阳性。
方法：她被诊断为骨关节炎和RA。全外显子组分析检测到2个罕见变异，c.4201C>T，p.(Arg1401Trp)和c4265C>T，p.(Pro1422Leu)，在COL11A2基因(NM_080680.2)中。具有长插入片段大小的全基因组分析证实了2个反式变体。
结果：她接受了人工耳蜗,这改善了她的听力。她接受了甲氨蝶呤治疗,戈利木单抗,托珠单抗,和upadacitinib对她的RA有部分反应。
结论:我们在此报道了患有RA的患者,其在COL11A2基因中具有复合杂合变体。在RA患者血清中检测到抗XI型胶原的自身抗体，提示XI型胶原可能作为自身抗原参与RA的发病。该患者的听力损失和骨关节炎可能是由于COL11A2基因中的复合杂合变体，变异体诱导的构象变化可能改变了XI型胶原的免疫原性,导致RA的发展。
方法：患者是一名60岁的女性，出生于没有血缘关系的日本父母。她从小就有进行性听力损失。她的父亲在中年之前也有进行性听力损失。她四十多岁时膝盖和臀部出现关节痛。56岁时，她患上了多关节炎。类风湿因子和抗CCP抗体阳性。
方法：她被诊断为骨关节炎和RA。全外显子组分析检测到2个罕见变异，c.4201C>T，p.(Arg1401Trp)和c4265C>T，p.(Pro1422Leu)，在COL11A2基因(NM_080680.2)中。具有长插入片段大小的全基因组分析证实了2个反式变体。
结果：她接受了人工耳蜗,这改善了她的听力。她接受了甲氨蝶呤治疗,戈利木单抗,托珠单抗,和upadacitinib对她的RA有部分反应。
结论:我们在此报道了患有RA的患者,其在COL11A2基因中具有复合杂合变体。在RA患者血清中检测到抗XI型胶原的自身抗体，提示XI型胶原可能作为自身抗原参与RA的发病。该患者的听力损失和骨关节炎可能是由于COL11A2基因中的复合杂合变体，变异体诱导的构象变化可能改变了XI型胶原的免疫原性,导致RA的发展。
