A novel de novo NLRC4 mutation reinforces the likely pathogenicity of specific LRR domain mutation
A novel de novo NLRC4 mutation reinforces the likely pathogenicity of specific LRR domain mutation
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DOI：
10.1016/j.clim.2019.108328
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发表时间：
2020-02-01
影响因子：
8.6
通讯作者：
Bin Mohamad, Saharuddin
中科院分区：
文献类型：
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作者：
Chear, Chai Teng;Nallusamy, Revathy;Bin Mohamad, Saharuddin
自身炎症性疾病的特点是先天免疫反应失调，导致反复出现不受控制的全身炎症和发烧。 NLRC4 的功能获得性突变已被描述可引起一系列自身炎症性疾病。我们报告一名十二岁的马来女孩患有反复发烧、皮肤红斑和炎性关节炎。全外显子组测序和随后的双向 Sanger 测序鉴定出 NLRC4 中的杂合错义突变 (NM_001199138: c.1970A > T)。这种变异在计算机上被预测具有破坏性，在公共和本地数据库中不存在，并且发生在富含亮氨酸重复序列 (LRR) 结构域的高度保守残基中。细胞因子分析显示血清IL-18和IL-18/CXCL9比率极高，与其他NLRC4-MAS患者一致。总之，我们在马来西亚发现了首例患有导致自身炎症性疾病的新型杂合 NLRC4 基因突变的患者。我们的研究结果强化了 NLRC4 中特定 LRR 结构域突变的可能致病性，并扩大了 NLRC4 突变的临床谱。
Autoinflammatory disorders are characterized by dysregulated innate immune response, resulting in recurrent uncontrolled systemic inflammation and fever. Gain-of-function mutations in NLRC4 have been described to cause a range of autoinflammatory disorders. We report a twelve-year-old Malay girl with recurrent fever, skin erythema, and inflammatory arthritis. Whole exome sequencing and subsequent bidirectional Sanger sequencing identified a heterozygous missense mutation in NLRC4 (NM_001199138: c.1970A > T). This variant was predicted to be damaging in silico, was absent in public and local databases and occurred in a highly conserved residue in the leucine-rich repeat (LRR) domain. Cytokine analysis showed extremely high serum IL-18 and IL-18/CXCL9 ratio, consistent with other NLRC4-MAS patients. In summary, we identified the first patient with a novel de novo heterozygous NLRC4 gene mutation contributing to autoinflammatory disease in Malaysia. Our findings reinforce the likely pathogenicity of specific LRR domain mutations in NLRC4 and expand the clinical spectrum of NLRC4 mutations.