Tanaka Naoko, Izawa Kazushi, Saito Megumu K, Sakuma Mio, Oshima Koichi, Ohara Osamu, Nishikomori Ryuta, Morimoto Takeshi, Kambe Naotomo, Goldbach-Mansky Raphaela, Aksentijevich Ivona, de Saint Basile Geneviève, Neven Bénédicte, van Gijn Mariëlle, Frenkel Joost, Aróstegui Juan I, Yagüe Jordi, Merino Rosa, Ibañez Mercedes, Pontillo Alessandra, Takada Hidetoshi, Imagawa Tomoyuki, Kawai Tomoki, Yasumi Takahiro, Nakahata Tatsutoshi, Heike Toshio
Kyoto University Graduate School of Medicine, Kyoto, Japan.
Arthritis Rheum. 2011 Nov;63(11):3625-32. doi: 10.1002/art.30512.
Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in ∼40% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation-negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome.
An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype-phenotype associations.
Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2%). Estimates of the level of mosaicism ranged from 4.2% to 35.8% (mean ± SD 12.1 ± 7.9%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms.
Somatic NLRP3 mutations were identified in 69.2% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome.
慢性婴儿神经皮肤关节综合征（CINCA），也称为新生儿期起病的多系统炎症性疾病（NOMID），是一种常染色体显性遗传的全身性自身炎症性疾病。虽然杂合子种系功能获得性NLRP3突变是该疾病的已知病因，但传统基因分析在约40%的患者中未能检测到致病突变。由于在一些突变阴性的NOMID/CINCA综合征患者中检测到了体细胞NLRP3镶嵌现象，我们开展了本研究以确定体细胞NLRP3镶嵌现象对NOMID/CINCA综合征病因的确切作用。
开展一项国际病例对照研究，以检测在传统测序中未显示突变的NOMID/CINCA综合征患者中的体细胞NLRP3镶嵌现象。对这些突变阴性的NOMID/CINCA综合征患者及其健康亲属进行NLRP3的亚克隆和测序。分析临床特征以确定潜在的基因型-表型关联。
26例患者中有18例（69.2%）检测到体细胞NLRP3镶嵌现象。镶嵌水平估计范围为4.2%至35.8%（均值±标准差12.1±7.9%）。19名健康亲属中均未检测到镶嵌现象（26例患者中的18例与19名亲属中的0例；P<0.0001）。体外功能试验表明，检测到的体细胞NLRP3突变具有致病性功能效应。不同细胞谱系之间未检测到NLRP3镶嵌现象的差异。在未描述的临床特征中，体细胞镶嵌患者的智力发育迟缓发生率较低。基因型匹配比较证实，体细胞NLRP3镶嵌患者的神经症状较轻。
在69.2%的突变阴性NOMID/CINCA综合征患者中鉴定出体细胞NLRP3突变。这表明体细胞NLRP3镶嵌现象是NOMID/CINCA综合征的主要病因。
