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

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.

%B Arthritis Rheum %V 63 %P 3625-32 %8 2011 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21702021?dopt=Abstract %R 10.1002/art.30512