Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM
Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM
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DOI：
10.1073/pnas.221456898
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发表时间：
2001-10-23
影响因子：
11.1
通讯作者：
Plebani, A
中科院分区：
文献类型：
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作者：
Ferrari, S;Giliani, S;Plebani, A
CD40是肿瘤坏死因子受体超家族的成员，表达于多种细胞类型，包括B细胞、巨噬细胞和树突状细胞。CD40是CD40配体(CD40L)的受体，CD40L是一种主要由活化的CD4(+)T细胞表达的分子。CD40/CD40L相互作用诱导记忆B淋巴细胞的形成并促进Ig同型转换，这在CD40L或CD40基因敲除的小鼠中得到证实，在X连锁高IgM综合征患者中得到证实，这是一种由CD40L/TNFSF5基因突变引起的疾病。在目前的研究中，我们已经确认了三名常染色体隐性高IgM患者，他们不能表达细胞表面的CD40。CD40基因组DNA序列分析显示，1例患者携带外显子5第5碱基对位置的纯合子沉默突变，涉及外显子剪接增强子，导致外显子跳跃和提前终止；另2例患者在外显子3存在纯合点突变，导致半胱氨酸替换为精氨酸。这些发现表明，CD40基因的突变导致了常染色体隐性的高IgM，在免疫和临床上与X连锁的高IgM无法区分。
CD40 is a member of the tumor necrosis factor receptor superfamily, expressed on a wide range of cell types including B cells, macrophages, and dendritic cells. CD40 is the receptor for CD40 ligand (CD40L), a molecule predominantly expressed by activated CD4(+) T cells. CD40/CD40L interaction induces the formation of memory B lymphocytes and promotes Ig isotype switching, as demonstrated in mice knocked-out for either CD40L or CD40 gene, and in patients with X-linked hyper IgM syndrome, a disease caused by CD40L/TNFSF5 gene mutations. In the present study, we have identified three patients with an autosomal recessive form of hyper IgM who fail to express CD40 on the cell surface. Sequence analysis of CD40 genomic DNA showed that one patient carried a homozygous silent mutation at the fifth base pair position of exon 5, involving an exonic splicing enhancer and leading to exon skipping and premature termination; the other two patients showed a homozygous point mutation in exon 3, resulting in a cysteine to arginine substitution. These findings show that mutations of the CD40 gene cause an autosomal recessive form of hyper IgM, which is immunologically and clinically undistinguishable from the X-linked form.