TY - JOUR T1 - High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. JF - Arthritis Rheum Y1 - 2011 A1 - Tanaka, Naoko A1 - Izawa, Kazushi A1 - Saito, Megumu K A1 - Sakuma, Mio A1 - Oshima, Koichi A1 - Ohara, Osamu A1 - Nishikomori, Ryuta A1 - Morimoto, Takeshi A1 - Kambe, Naotomo A1 - Goldbach-Mansky, Raphaela A1 - Aksentijevich, Ivona A1 - de Saint Basile, Geneviève A1 - Neven, Bénédicte A1 - van Gijn, Mariëlle A1 - Frenkel, Joost A1 - Aróstegui, Juan I A1 - Yagüe, Jordi A1 - Merino, Rosa A1 - Ibañez, Mercedes A1 - Pontillo, Alessandra A1 - Takada, Hidetoshi A1 - Imagawa, Tomoyuki A1 - Kawai, Tomoki A1 - Yasumi, Takahiro A1 - Nakahata, Tatsutoshi A1 - Heike, Toshio KW - Adolescent KW - Adult KW - Carrier Proteins KW - Case-Control Studies KW - Child KW - Child, Preschool KW - Cryopyrin-Associated Periodic Syndromes KW - Female KW - Genetic Association Studies KW - Humans KW - Infant KW - Male KW - Mosaicism AB -

OBJECTIVE: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

VL - 63 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21702021?dopt=Abstract ER -