Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.
Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.
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DOI：
10.1084/jem.20191804
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发表时间：
2020-06-01
期刊：
影响因子：
--
通讯作者：
Puel A
中科院分区：
文献类型：
--
作者：
Béziat V;Tavernier SJ;Chen YH;Ma CS;Materna M;Laurence A;Staal J;Aschenbrenner D;Roels L;Worley L;Claes K;Gartner L;Kohn LA;De Bruyne M;Schmitz-Abe K;Charbonnier LM;Keles S;Nammour J;Vladikine N;Maglorius Renkilaraj MRL;Seeleuthner Y;Migaud M;Rosain J;Jeljeli M;Boisson B;Van Braeckel E;Rosenfeld JA;Dai H;Burrage LC;Murdock DR;Lambrecht BN;Avettand-Fenoel V;Vogel TP;Undiagnosed Diseases Network;Esther CR;Haskologlu S;Dogu F;Ciznar P;Boutboul D;Ouachée-Chardin M;Amourette J;Lebras MN;Gauvain C;Tcherakian C;Ikinciogullari A;Beyaert R;Abel L;Milner JD;Grimbacher B;Couderc LJ;Butte MJ;Freeman AF;Catherinot É;Fieschi C;Chatila TA;Tangye SG;Uhlig HH;Haerynck F;Casanova JL;Puel A
STAT3的显性阴性变异并不能解释常染色体显性遗传性高IgE综合征(HIEs)的所有病例。Béziat等人。报道了编码gp130受体的IL6ST显性-负性变异的HIE患者，通常在IL-6和相关细胞因子的刺激下招募STAT3。常染色体显性遗传性高IgE综合征(AD-HIEs)通常由显性-阴性(DN)STAT3突变引起。患者患有感冒葡萄球菌皮损和皮肤粘膜念珠菌病，严重过敏和骨骼异常。我们报告了来自8个无关家系的12例AD-HIES患者，这些患者是由DNIL6ST突变引起的。我们确定了七种不同的截断突变，其中一种是反复发生的。突变的等位基因编码带有跨膜区的gp130受体，但缺乏循环基序和所有四个招募STAT3的酪氨酸残基。当过表达时，突变蛋白在细胞表面积累，并失去对IL-6、IL-11、LIF和OSM的细胞反应的功能和DN。此外，患者的杂合子白细胞和成纤维细胞对IL-6和IL-11的反应较差。STAT3和IL6ST突变的患者一贯表现出IL-6R缺乏的感染性和过敏性表现，以及IL-11R缺乏的一些骨骼异常。因此，DNSTAT3和IL6ST突变似乎通过损害IL-6和IL-11反应通路而成为临床表型的基础。
Dominant-negative variants of STAT3 do not account for all cases of autosomal dominant hyper-IgE syndrome (HIES). Béziat et al. report HIES patients with dominant-negative variations of IL6ST, encoding the GP130 receptor, which normally recruits STAT3 upon stimulation with IL-6 and related cytokines. Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.
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