Dominant-negative STAT1 SH2 domain mutations in unrelated patients with Mendelian susceptibility to mycobacterial disease.
Dominant-negative STAT1 SH2 domain mutations in unrelated patients with Mendelian susceptibility to mycobacterial disease.
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DOI：
10.1002/humu.22113
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发表时间：
2012-09
期刊：
影响因子：
3.9
通讯作者：
Kobayashi, Masao
中科院分区：
文献类型：
--
作者：
Tsumura, Miyuki;Okada, Satoshi;Sakai, Hidemasa;Yasunaga, Shin'ichiro;Ohtsubo, Motoaki;Murata, Takuji;Obata, Hideto;Yasumi, Takahiro;Kong, Xiao-Fei;Abhyankar, Avinash;Heike, Toshio;Nakahata, Tatsutoshi;Nishikomori, Ryuta;Al-Muhsen, Saleh;Boisson-Dupuis, Stephanie;Casanova, Jean-Laurent;AlZahrani, Mofareh;Al Shehri, Mohammed;ElGhazali, Geyhad;Takihara, Yoshihiro;Kobayashi, Masao
携带两个功能缺失（或半形）STAT1等位基因的患者易患细胞内细菌和病毒疾病。STAT1中功能缺失显性阴性突变的杂合性导致常染色体显性（AD）对分枝杆菌病（MSMD）的孟德尔易感性，而功能缺失去磷酸化突变的杂合性导致AD慢性粘膜皮肤念珠菌病（CMC）。先前报道的两种引起AD msmd的STAT1突变类型位于尾部结构域（p.L706S）或dna结合结构域（p.E320Q和p.Q463H），而引起AD cmc的突变位于螺旋结构域。我们在来自日本和沙特阿拉伯的两名不相关的患者中发现了两例AD-STAT1缺乏症，他们携带影响SH2结构域的杂合错义突变（p.K637E和p.K673R）。p.K673R是一种亚形态突变，会损害STAT1酪氨酸磷酸化，而p.K637E突变是无效的，会影响STAT1磷酸化和dna结合活性。这两个等位基因均为显性阴性，导致stat1介导的细胞对IFN-γ和IL-27的反应受损。相比之下，stat1介导的细胞对IFN-α和IFN-λ1的反应在患者细胞中保持在正常水平。我们在这里描述了STAT1的SH2结构域的第一个显性突变，揭示了该结构域对酪氨酸磷酸化和dna结合以及抗分枝杆菌免疫的重要性。
Patients carrying two loss-of-function (or hypomorphic) alleles of STAT1 are vulnerable to intracellular bacterial and viral diseases. Heterozygosity for loss-of-function dominant-negative mutations in STAT1 is responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD), whereas heterozygosity for gain-of-function loss-of-dephosphorylation mutations causes AD chronic mucocutaneous candidiasis (CMC). The two previously reported types of AD MSMD-causing STAT1 mutations are located in the tail domain (p.L706S) or in the DNA-binding domain (p.E320Q and p.Q463H), whereas the AD CMC-causing mutations are located in the coiled-coil domain. We identified two cases with AD-STAT1 deficiency in two unrelated patients from Japan and Saudi Arabia carrying heterozygous missense mutations affecting the SH2 domain (p.K637E and p.K673R). p.K673R is a hypomorphic mutation that impairs STAT1 tyrosine phosphorylation, whereas the p.K637E mutation is null and affects both STAT1 phosphorylation and DNA-binding activity. Both alleles are dominant-negative and result in impaired STAT1-mediated cellular responses to IFN-γ and IL-27. By contrast, STAT1-mediated cellular responses against IFN-α and IFN-λ1 were preserved at normal levels in patients’ cells. We describe here the first dominant mutations in the SH2 domain of STAT1, revealing the importance of this domain for tyrosine phosphorylation and DNA-binding, as well as for anti-mycobacterial immunity.
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影响因子：
30.8
作者：
Dupuis, S;Jouanguy, E;Casanova, JL
通讯作者：
Casanova, JL
影响因子：
15.9
作者：
Jouanguy, E;Dupuis, S;Casanova, JL
通讯作者：
Casanova, JL
影响因子：
4.4
作者：
Chapgier, Ariane;Wynn, Robert F.;Arkwright, Peter D.
通讯作者：
Arkwright, Peter D.
影响因子：
56.9
作者：
Kim, TK;Maniatis, T
通讯作者：
Maniatis, T
X连锁对分枝杆菌的敏感性是由NEMO中的突变损害CD40依赖性IL-12产生引起的。
影响因子：
15.3
作者：
Filipe-Santos, Orchidee;Bustamante, Jacinta;Haverkamp, Margje H;Vinolo, Emilie;Ku, Cheng-Lung;Puel, Anne;Frucht, David M;Christel, Karin;von Bernuth, Horst;Jouanguy, Emmanuelle;Feinberg, Jacqueline;Durandy, Anne;Senechal, Brigitte;Chapgier, Ariane;Vogt, Guillaume;de Beaucoudrey, Ludovic;Fieschi, Claire;Picard, Capucine;Garfa, Meriem;Chemli, Jalel;Bejaoui, Mohamed;Tsolia, Maria N;Kutukculer, Necil;Plebani, Alessandro;Notarangelo, Luigi;Bodemer, Christine;Geissmann, Frederic;Israel, Alain;Veron, Michel;Knackstedt, Maike;Barbouche, Ridha;Abel, Laurent;Magdorf, Klaus;Gendrel, Dominique;Agou, Fabrice;Holland, Steven M;Casanova, Jean-Laurent
通讯作者：
Casanova, Jean-Laurent