A Somatic NLRP3 Mutation as a Cause of a Sporadic Case of Chronic Infantile Neurologic, Cutaneous, Articular Syndrome/Neonatal-Onset Multisystem Inflammatory Disease Novel Evidence of the Role of Low-Level Mosaicism as the Pathophysiologic Mechanism Underlying Mendelian Inherited Diseases
A Somatic NLRP3 Mutation as a Cause of a Sporadic Case of Chronic Infantile Neurologic, Cutaneous, Articular Syndrome/Neonatal-Onset Multisystem Inflammatory Disease Novel Evidence of the Role of Low-Level Mosaicism as the Pathophysiologic Mechanism Underlying Mendelian Inherited Diseases
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DOI：
10.1002/art.27342
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发表时间：
2010-04-01
影响因子：
--
通讯作者：
Yaguee, Jordi
中科院分区：
文献类型：
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作者：
Arostegui, Juan I.;Lopez Saldana, Ma Dolores;Yaguee, Jordi
Objective.慢性婴儿神经、皮肤、关节综合征（CINCA），也称为脑源性多系统炎性疾病（NOMID），是一种严重的早发性自身炎性疾病，其特征为荨麻疹样皮疹、关节炎/关节病、可变神经受累和畸形特征，通常对白细胞介素-1阻断有反应。CINCA/NOMID与显性孟德尔遗传NLRP 3突变相关。然而，常规测序分析仅在55-60%的患者中检测到真正的致病突变，这表明存在遗传异质性。我们进行了目前的研究，以评估存在的体细胞，nongermline NLRP 3突变的散发病例CINCA/NOMID. Methods。通过直接访谈收集临床数据、实验室结果和治疗结果信息。进行详尽的遗传学研究，包括桑格法测序、亚克隆、限制性片段长度多态性分析和焦磷酸测序。根据临床特征（疾病早期发作、荨麻疹样皮疹、膝关节病和畸形特征）诊断患者的CINCA/NOMID。患者在过去28个月内对阿那白滞素表现出成功的反应。NLRP 3的分析鉴定了一种新的杂合变体（p.D303H），其在类似于30-38%的循环白细胞中检测到。在健康对照组和患者父母中没有这种变异，这表明这是一种真正的从头致病突变。进一步的分析表明，这种新的突变存在于白细胞亚群和上皮细胞。我们的研究结果确定了西班牙CINCA/NOMID患者中的新型p.D303H NLRP 3变体是一种新的致病突变，该突变在造血和非造血细胞谱系中被检测为体细胞非胚系突变。我们的数据提供了新的见解的作用，低水平的镶嵌在NLRP 3作为病理生理机制的基础cryopyrin相关的周期性综合征。
Objective. Chronic infantile neurologic, cutaneous, articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID), is a severe, early-onset autoinflammatory disease characterized by an urticaria-like rash, arthritis/arthropathy, variable neurologic involvement, and dysmorphic features, which usually respond to interleukin-1 blockade. CINCA/NOMID has been associated with dominant Mendelian inherited NLRP3 mutations. However, conventional sequencing analyses detect true disease-causing mutations in only similar to 55-60% of patients, which suggests the presence of genetic heterogeneity. We undertook the current study to assess the presence of somatic, nongermline NLRP3 mutations in a sporadic case of CINCA/NOMID.Methods. Clinical data, laboratory results, and information on treatment outcomes were gathered through direct interviews. Exhaustive genetic studies, including Sanger method sequencing, subcloning, restriction fragment length polymorphism assay, and pyrosequencing, were performed.Results. The patient's CINCA/NOMID was diagnosed based on clinical features (early onset of the disease, urticaria-like rash, knee arthropathy, and dysmorphic features). The patient has exhibited a successful response to anakinra within the last 28 months. Analysis of NLRP3 identified a novel heterozygous variant (p.D303H) that was detected in similar to 30-38% of circulating leukocytes. The absence of this variant in healthy controls and in the patient's parents suggested a de novo true disease-causing mutation. Additional analyses showed that this novel mutation was present in both leukocyte subpopulations and epithelial cells.Conclusion. Our findings identify the novel p.D303H NLRP3 variant in a Spanish patient with CINCA/NOMID as a new disease-causing mutation, which was detected as a somatic, nongermline mutation in hematopoietic and nonhematopoietic cell lineages. Our data provide new insight into the role of low-level mosaicism in NLRP3 as the pathophysiologic mechanism underlying cryopyrin-associated periodic syndrome.