High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study.
High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study.
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慢性婴儿神经系统，皮肤，关节综合征的患者NLRP3体细胞镶嵌的发病率很高：国际多中心协作研究的结果。
DOI：
10.1002/art.30512
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发表时间：
2011-11
影响因子：
--
通讯作者：
Heike, Toshio
中科院分区：
文献类型：
--
作者：
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, Genevieve;Neven, Benedicte;van Gijn, Marielle;Frenkel, Joost;Arostegui, Juan I.;Yaguee, Jordi;Merino, Rosa;Ibanez, Mercedes;Pontillo, Alessandra;Takada, Hidetoshi;Imagawa, Tomoyuki;Kawai, Tomoki;Yasumi, Takahiro;Nakahata, Tatsutoshi;Heike, Toshio
慢性婴儿神经、皮肤、关节综合征（CINCA），又称脑源性多系统炎性疾病（NOMID），是一种显性遗传的全身性自身炎性疾病。尽管杂合子生殖系功能获得性NLRP 3突变是这种疾病的已知原因，但常规遗传分析无法在约40%的患者中检测到致病突变。由于体细胞NLRP 3嵌合体已在几个突变阴性的NOMID/CINCA综合征患者中检测到，我们进行了这项研究，以确定体细胞NLRP 3嵌合体的NOMID/CINCA综合征的病因学的确切贡献。进行了一项国际病例对照研究，以检测在常规测序期间未显示突变的NOMID/CINCA综合征患者的体细胞NLRP 3嵌合现象。在这些突变阴性的NOMID/CINCA综合征患者及其健康亲属中进行NLRP 3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。在26例患者中的18例（69.2%）中确定了体细胞NLRP 3嵌合体。镶嵌性水平的估计值范围为4.2%至35.8%（平均值± SD 12.1 ± 7.9%）。在19名健康亲属中均未检测到嵌合体（26名患者中的18名与19名亲属中的0名; P < 0.0001）。体外功能测定表明，检测到的体细胞NLRP 3突变具有致病功能效应。在不同细胞系之间未检测到NLRP 3嵌合体的差异。在无法描述的临床特征中，注意到躯体嵌合体患者的精神发育迟滞发生率较低。基因型匹配比较证实，体细胞NLRP 3嵌合体的患者表现出较轻的神经系统症状。在69.2%的突变阴性NOMID/CINCA综合征患者中发现了体细胞NLRP 3突变。这表明体细胞NLRP 3嵌合体是NOMID/CINCA综合征的主要原因。
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.
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影响因子：
3.9
作者：
Milhavet, Florian;Cuisset, Laurence;Touitou, Isabelle
通讯作者：
Touitou, Isabelle
影响因子：
--
作者：
Arostegui, Juan I.;Lopez Saldana, Ma Dolores;Yaguee, Jordi
通讯作者：
Yaguee, Jordi
影响因子：
--
作者：
Saito, M;Fujisawa, A;Nakahata, T
通讯作者：
Nakahata, T
影响因子：
20.3
作者：
Saito, Megumu;Nishikomori, Ryuta;Nakahata, Tatsutoshi
通讯作者：
Nakahata, Tatsutoshi
影响因子：
20.3
作者：
Neven, B;Callebaut, I;Saint Basile, GD
通讯作者：
Saint Basile, GD