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

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• 作者：Gabriela Lopez-Herrera¹ ; ² ; Giacomo Tampella³ ; ¹⁹ ; Qiang Pan-Hammarströ ; m⁴ ; ¹⁹ ; Peer Herholz⁵ ; ¹⁹ ; Claudia  ; M. Trujillo-Vargas¹ ; ⁶ ; ¹⁹ ; Kanchan Phadwal⁷ ; Anna  ; Katharina Simon⁷ ; ⁸ ; Michel Moutschen⁹ ; Amos Etzioni¹⁰ ; Adi Mory¹⁰ ; Izhak Srugo¹⁰ ; Doron Melamed¹⁰ ; Kjell Hultenby⁴ ; Chonghai Liu⁴ ; ¹¹ ; Manuela Baronio³ ; Massimiliano Vitali³ ; Pierre Philippet¹² ; Vinciane Dideberg¹³ ; Asghar Aghamohammadi¹⁴ ; Nima Rezaei¹⁵ ; Victoria Enright¹ ; Likun Du⁴ ; Ulrich Salzer⁵ ; Hermann Eibel⁵ ; Dietmar Pfeifer¹⁶ ; Hendrik Veelken¹⁷ ; Hans Stauss¹ ; Vassilios Lougaris³ ; Alessandro Plebani³ ; E.  ; Michael Gertz¹⁸ ; Alejandro  ; A. Schä ; ffer¹⁸ ; Lennart Hammarströ ; m⁴ ; Bodo Grimbacher¹ ; ⁵ ; ^{bodo.grimbacher@uniklinik-freiburg.de}
• 刊名：The American Journal of Human Genetics
• 出版年：2012
• 期刊代码：P22_00029297
• 类别：bio
• 出版时间：8 June, 2012
• 卷：90
• 期：6
• 页码：986-1001
• 文件大小：1329 K

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聽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.