Deleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity

被引:380
作者
Lopez-Herrera, Gabriela [1 ,2 ]
Tampella, Giacomo [3 ,4 ]
Pan-Hammarstrom, Qiang [5 ]
Herholz, Peer [6 ]
Trujillo-Vargas, Claudia M. [1 ,7 ]
Phadwal, Kanchan [8 ]
Simon, Anna Katharina [8 ,9 ]
Moutschen, Michel [10 ]
Etzioni, Amos [11 ]
Mory, Adi [11 ]
Srugo, Izhak [11 ]
Melamed, Doron [11 ]
Hultenby, Kjell [5 ]
Liu, Chonghai [5 ,12 ]
Baronio, Manuela [3 ,4 ]
Vitali, Massimiliano [3 ,4 ]
Philippet, Pierre [13 ]
Dideberg, Vinciane [14 ]
Aghamohammadi, Asghar [15 ]
Rezaei, Nima [16 ,17 ]
Enright, Victoria [1 ]
Du, Likun [5 ]
Salzer, Ulrich [6 ]
Eibel, Hermann [6 ]
Pfeifer, Dietmar [18 ]
Veelken, Hendrik [19 ]
Stauss, Hans [1 ]
Lougaris, Vassilios [3 ,4 ]
Plebani, Alessandro [3 ,4 ]
Gertz, E. Michael [20 ]
Schaeffer, Alejandro A. [20 ]
Hammarstrom, Lennart [5 ]
Grimbacher, Bodo [1 ,6 ]
机构
[1] UCL, Royal Free Hosp, Div Infect & Immun, Dept Immunol, London NW3 2QG, England
[2] Natl Inst Pediat, Immunodeficiency Res Unit, Mexico City 04530, DF, Mexico
[3] Univ Brescia, Pediat Clin, Spedali Civili Brescia, I-25123 Brescia, Italy
[4] Univ Brescia, Inst Mol Med A Novicelli, Spedali Civili Brescia, I-25123 Brescia, Italy
[5] Karolinska Inst, Karolinska Univ Hosp Huddinge, Dept Lab Med, SE-14186 Stockholm, Sweden
[6] Univ Med Ctr, Ctr Chron Immunodeficiency, D-79108 Freiburg, Germany
[7] Univ Antioquia, Grp Primary Immunodeficiencies, Medellin 1226, Colombia
[8] Univ Oxford, Biomed Res Ctr Translat Immunol Lab, Natl Inst Hlth Res, Nuffield Dept Med,John Radcliffe Hosp, Oxford OX3 9DS, England
[9] Univ Oxford, Medcial Res Council Human Immunol Unit, Weatherall Inst Mol Med, John Radcliffe Hosp, Oxford OX3 9DS, England
[10] Univ Liege, Ctr Immunol, Lab Immunoendocrinol, Inst Pathol, B-4000 Liege, Belgium
[11] Technion Israel Inst Technol, Rappaport Sch Med, Div Pediat & Immunol, IL-31096 Haifa, Israel
[12] N Sichuan Med Coll, Affiliated Hosp, Dept Pediat, Nanchong 637000, Sichuan, Peoples R China
[13] Ctr Hosp Chretien Esperance, Dept Pediat, B-4420 Montegnee, Belgium
[14] Univ Liege, Ctr Human Genet, B-4000 Liege, Belgium
[15] Univ Tehran Med Sci, Childrens Med Ctr, Pediat Ctr Excellence, Res Ctr Immunodeficiencies, Tehran 14194, Iran
[16] Univ Tehran Med Sci, Sch Med, Mol Immunol Res Ctr, Tehran 14194, Iran
[17] Univ Tehran Med Sci, Sch Med, Dept Immunol, Tehran 14194, Iran
[18] Univ Freiburg, Med Ctr, Dept Hematol & Oncol, D-79106 Freiburg, Germany
[19] Leiden Univ, Med Ctr, Dept Hematol, NL-2300 RC Leiden, Netherlands
[20] NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Bethesda, MD 20894 USA
基金
欧洲研究理事会; 美国国家卫生研究院; 瑞典研究理事会; 英国医学研究理事会; 英国生物技术与生命科学研究理事会;
关键词
COMMON VARIABLE IMMUNODEFICIENCY; X-LINKED AGAMMAGLOBULINEMIA; SELECTIVE IGA DEFICIENCY; LARGE COHORT; AUTOPHAGY; PROTEIN; GENE; FAMILY; PATHOGENESIS; LINKAGE;
D O I
10.1016/j.ajhg.2012.04.015
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.
引用
收藏
页码:986 / 1001
页数:16
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