Nat Genet:单基因突变导致过敏性皮炎的发生  

Germline hypomorphic CARD11 mutations in severe atopic disease

作　　者：Chi A Ma, Yuan Zhang, Michael A Weinreich, Jonathan J Lyons, Celeste G Nelson, Thomas DiMaggio, Kelly D Stone, Joshua D Milner Jeffrey R Stinson, Elisa Ruffo, Batsukh Dorjbal, Swadhinya Arjunaraja, Kelsey Voss, Andrew L Snow Jordan K Abbott, Pia J Hauk, Paul R Reynolds, Erwin W Gelfand Elisa Ruffo Salomé Glauzy, Natsuko Yamakawa, Eric Meffre Jennifer Stoddard, Julie Niemela, Sergio D Rosenzweig Yu Zhang, Helen F Matthews Joshua J McElwee Nina Jones Alejandro Palma, Matías Oleastro, Emma Prieto, Andrea R Bernasconi, Geronimo Dubra, Silvia Danielian, Jonathan Zaiat, Marcelo A Marti Brian Kim Megan A Cooper Neil Romberg 

机构地区：[1]Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA [2]Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA [3]Immunodeficiency Diagnosis and Treatment Program, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA [4]Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy [5]Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA [6]Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA [7]Human Immunological Disease Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA [8]Merck Research Laboratories, Merck and Co., Inc., Boston, Massachusetts, USA [9]Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., NCI Campus at Frederick, Frederick, Maryland, USA [10]Servicio de Immunología y Reumatología, Hospital Nacional de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina [11]Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA [12]Department of Pediatrics, Division of Rheumatology and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA [13]Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

出　　处：《现代生物医学进展》2017年第27期I0004-I0004,共1页Progress in Modern Biomedicine

摘　　要：最近，研究者们鉴定出了一类导致神经性皮炎发生的关键基因突变：CARDll。来自美国NIH过敏与传染病研究所的研究者们通过对四个没有血缘关系的患病家庭进行分析，发现了这一导致疾病产生的基因、Few monogenic causes for severe manifestations of common allergic diseases have been identified. Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11, which encodes a scaffolding protein involved in lymphocyte receptor signaling. Disease improved over time in most patients. Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor-induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1). Patient T cells had similar defects, as well as low production of the cytokine interferon-γ (IFN-γ). The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells. Our findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects that lead to atopic dermatitis.

关 键 词：过敏性皮炎 基因突变 NAT 神经性皮炎 血缘关系 研究所 传染病 NIH 

分 类 号：Q754[生物学—分子生物学]