title: Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic, cutaneous, articular syndrome.
abstract: Chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) is a severe inflammatory disease that was recently found to be associated with mutations in CIAS1. However, CIAS1 mutations have been detected in only half of CINCA syndrome patients, and it remains unclear which genes are responsible for the syndrome in the remaining patients. We describe here a patient with CINCA syndrome who exhibited CIAS1 somatic mosaicism. We genetically analyzed the CIAS1 gene in various blood cells and the buccal mucosa of the patient. The production of interleukin-1beta (IL-1beta) by peripheral blood mononuclear cells (PBMCs) was measured by enzyme-linked immunosorbent assay, and the ability of the mutant CIAS1 gene to enhance ASC-dependent NF-kappaB activation was assessed to confirm that the mutations of CIAS1 found were responsible for the patient's clinical manifestations of the CINCA syndrome. The patient had 1 heterologous single-nucleotide polymorphism, 587G>A (S196N), and 1 heterologous mutation, 1709A>G (Y570C), in exon 3 of CIAS1. The latter mutation was found to occur as somatic mosaicism. The patient's PBMCs produced a large amount of IL-1beta in the absence of stimulation, unlike those from controls or from his mother, who also bore the S196N polymorphism. In addition, the Y570C mutation (with or without the S196N polymorphism) increased the ability of CIAS1 to induce ASC-dependent NF-kappaB activation, unlike the wild-type gene or the gene bearing the S196N polymorphism alone. The findings in this patient indicate that somatic mosaicism is one reason CIAS1 mutations have not been detected in some patients with CINCA syndrome.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Megumu
authors.initials: M
authors.lastname: Saito
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fujisawa
authors.forename: Ryuta
authors.initials: R
authors.lastname: Nishikomori
authors.forename: Naotomo
authors.initials: N
authors.lastname: Kambe
authors.forename: Mami
authors.initials: M
authors.lastname: Nakata-Hizume
authors.forename: Momoko
authors.initials: M
authors.lastname: Yoshimoto
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Ohmori
authors.forename: Ikuo
authors.initials: I
authors.lastname: Okafuji
authors.forename: Takakazu
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Takashi
authors.initials: T
authors.lastname: Kusunoki
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Miyachi
authors.forename: Toshio
authors.initials: T
authors.lastname: Heike
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
mesh_terms: D000293:Adolescent; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002908:Chronic Disease; D004252:DNA Mutational Analysis; D005260:Female; D005334:Fever; D006319:Hearing Loss, Sensorineural; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007375:Interleukin-1 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008581:Meningitis; D009030:Mosaicism; D016328:NF-kappa B / Q000096:biosynthesis; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010375:Pedigree; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome; D014581:Urticaria
chemical_list: D002352:Carrier Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human