Deleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity
Deleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity
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DOI：
10.1016/j.ajhg.2012.04.015
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发表时间：
2012-06-08
影响因子：
9.8
通讯作者：
Grimbacher, Bodo
中科院分区：
文献类型：
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作者：
Lopez-Herrera, Gabriela;Tampella, Giacomo;Grimbacher, Bodo
儿童期发作的低丙种球蛋白血症的常染色体遗传原因目前还不清楚。大多数受影响的个人是单纯的情况下，但常染色体显性和常染色体隐性遗传已被描述。我们对低丙种球蛋白血症的近亲家系进行了遗传连锁分析。四个具有儿童期发病的体液免疫缺陷和自身免疫特征的近亲家庭共享染色体4q上连锁间隔的基因型证据。位置候选基因的测序显示，在每个家庭中，受影响的个人有一个独特的纯合突变LRBA（脂多糖响应米色样锚蛋白）。所有LRBA突变与疾病分离，因为纯合子个体表现为低丙种球蛋白血症和自身免疫，而杂合子个体是健康的。这些突变在健康对照中不存在。具有纯合LRBA突变的个体没有LRBA，B细胞发育受到干扰，体外B细胞活化、浆母细胞形成和免疫球蛋白分泌缺陷，并且具有低增殖反应。我们的结论是，LRBA突变导致免疫缺陷的特点是缺陷的B细胞活化和自噬和细胞凋亡的敏感性，所有这些都与低丙种球蛋白血症和自身免疫的临床表型。
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.