Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome.
Early-onset sarcoidosis (EOS) and inheritable Blau syndrome (BS) share characteristic clinical features of juvenile-onset systemic granulomatosis syndrome that mainly affects skin, joints, and eyes. However, no direct evidence has been shown for the possible common origin of these 2 diseases. Recent discovery of CARD15 mutations in BS families encouraged us to investigate similar CARD15 mutations in EOS patients. Among 10 EOS cases retrospectively collected in Japan, heterozygous missense mutations were found in 9 cases; 4 showed a 1000C>T (R334W in amino acid change) that has been reported in BS, 4 showed novel 1487A>T (H496L), 1538T>C (M513T), 1813A>C (T605P), and 2010C>A (N670K), and 1 case showed double 1146C>G (D382E)/1834G>A (A612T) mutations on different alleles. All 6 of these variants of CARD15 showed increased basal nuclear factor (NF)-kappaB activity. These findings indicate that the majority of EOS and BS cases share the common genetic etiology of CARD15 mutations that cause constitutive NF-kappaB activation.
Kanazawa
Nobuo
N
Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Kyoto, Japan. nkanazaw@kuhp.kyoto-u.ac.jp
Okafuji
Ikuo
I
Kambe
Naotomo
N
Nishikomori
Ryuta
R
Nakata-Hizume
Mami
M
Nagai
Sonoko
S
Fuji
Akihiko
A
Yuasa
Takenosuke
T
Manki
Akira
A
Sakurai
Yoshihiko
Y
Nakajima
Mitsuru
M
Kobayashi
Hiroko
H
Fujiwara
Ikuma
I
Tsutsumi
Hiroyuki
H
Utani
Atsushi
A
Nishigori
Chikako
C
Heike
Toshio
T
Nakahata
Tatsutoshi
T
Miyachi
Yoshiki
Y
D017668:Age of Onset; D003424:Crohn Disease / Q000235:genetics; D005076:Exanthema / Q000235:genetics*; D005786:Gene Expression Regulation; D015812:Glaucoma, Angle-Closure / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012507:Sarcoidosis / Q000235:genetics*; D013577:Syndrome
D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein