Musculoskeletal Disease in MDA5-Related Type I Interferonopathy: A Mendelian Mimic of Jaccoud's Arthropathy.
Musculoskeletal Disease in MDA5-Related Type I Interferonopathy: A Mendelian Mimic of Jaccoud's Arthropathy.
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DOI：
10.1002/art.40179
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Crow YJ
中科院分区：
文献类型：
--
作者：
de Carvalho LM;Ngoumou G;Park JW;Ehmke N;Deigendesch N;Kitabayashi N;Melki I;Souza FFL;Tzschach A;Nogueira-Barbosa MH;Ferriani V;Louzada-Junior P;Marques W Jr;Lourenço CM;Horn D;Kallinich T;Stenzel W;Hur S;Rice GI;Crow YJ
明确手和足进行性肌肉骨骼疾病（包括弯曲趾、半脱位和肌腱断裂，使人联想到Jaccoud关节病）的多系统表型的分子基础。我们确定了2个分离常染色体显性表型的家族，包括肌肉骨骼疾病和可变的其他特征，包括银屑病、牙齿异常、心脏瓣膜受累、青光眼和基底节钙化。我们测量了外周血和皮肤中干扰素（IFN）刺激基因的表达，并对编码胞质双链RNA（dsRNA）传感器黑色素瘤分化相关蛋白5（MDA-5）的IFIH 1基因进行了靶向桑格测序。我们还在HEK 293 T细胞中使用体外IFNβ报告基因测定评估了IFIH 1基因变体的功能后果。我们记录了上调的I型干扰素诱导的基因转录在所有5名患者测试，并确定了一个杂合的功能获得性突变IFIH 1在每个家庭，导致不同的取代的MDA-5的位置331的苏氨酸残基。这两种变体均与在不存在外源性dsRNA配体的情况下IFNβ表达增加相关，与MDA-5的组成性激活一致。这些病例突出了与MDA-5突变相关的显著肌肉骨骼受累，并强调了IFN信号上调作为潜在分子病变标志物的检测价值。我们的数据表明，Singleton-Merten综合征和MDA-5功能获得性背景下描述的神经炎症构成了相同的I型干扰素病疾病谱的一部分，并提供了可能的新见解Jaccoud关节病的病理学。
To define the molecular basis of a multisystem phenotype with progressive musculoskeletal disease of the hands and feet, including camptodactyly, subluxation, and tendon rupture, reminiscent of Jaccoud’s arthropathy. We identified 2 families segregating an autosomal-dominant phenotype encompassing musculoskeletal disease and variable additional features, including psoriasis, dental abnormalities, cardiac valve involvement, glaucoma, and basal ganglia calcification. We measured the expression of interferon (IFN)-stimulated genes in the peripheral blood and skin, and undertook targeted Sanger sequencing of the IFIH1 gene encoding the cytosolic double-stranded RNA (dsRNA) sensor melanoma differentiation-associated protein 5 (MDA-5). We also assessed the functional consequences of IFIH1 gene variants using an in vitro IFNβ reporter assay in HEK293T cells. We recorded an up-regulation of type I IFN-induced gene transcripts in all 5 patients tested and identified a heterozygous gain-of-function mutation in IFIH1 in each family, resulting in different substitutions of the threonine residue at position 331 of MDA-5. Both of these variants were associated with increased IFNβ expression in the absence of exogenous dsRNA ligand, consistent with constitutive activation of MDA-5. These cases highlight the significant musculoskeletal involvement that can be associated with mutations in MDA-5, and emphasize the value of testing for up-regulation of IFN signaling as a marker of the underlying molecular lesion. Our data indicate that both Singleton-Merten syndrome and neuroinflammation described in the context of MDA-5 gain-of-function constitute part of the same type I interferonopathy disease spectrum, and provide possible novel insight into the pathology of Jaccoud’s arthropathy.
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DOI：
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发表时间：
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