Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Genet Med. 2012 Jan;14(1):81-9. doi: 10.1038/gim.0b013e3182310b7d. Epub 2011 Oct 7.
Autoimmune lymphoproliferative syndrome is a disorder of lymphocyte apoptosis. Although FAS molecules bearing mutations in the signal-transducing intracellular death domain exhibit dominant-negative interference with FAS-mediated apoptosis, mechanisms for pathology of non-death domain FAS mutations causing autoimmune lymphoproliferative syndrome are poorly defined.
RNA stability, protein expression, ligand binding, and ability to transmit apoptosis signals by anti-FAS antibody or FAS ligand were determined for a cohort of 39 patients with non-death domain autoimmune lymphoproliferative syndrome. Correlations between mutation type and disease penetrance were established in mutation-positive family members.
Frameshifts or transcriptional stop mutations before exon 7 resulted in messenger RNA haploinsufficiency, whereas an amino-terminal signal sequence mutation and certain intracellular truncations prevented cell surface localization of FAS. All resulted in decreased FAS localization, inability to bind FAS ligand, and reduced FAS ligand-induced apoptosis. Extracellular missense mutations and in-frame deletions expressed defective FAS protein, failed to bind FAS ligand, and exhibited dominant-negative interference with FAS-mediated apoptosis. Mutation-positive relatives with haploinsufficient or extracellular mutations had lower penetrance of autoimmune lymphoproliferative syndrome clinical phenotypes than did relatives with death domain mutations.
We have defined molecular mechanisms by which non-death domain FAS mutations result in reduced lymphocyte apoptosis, established a hierarchy of genotype-phenotype correlation among mutation-positive relatives of patients with autoimmune lymphoproliferative syndrome, and demonstrated that FAS haploinsufficiency can lead to autoimmune lymphoproliferative syndrome.
自身免疫性淋巴细胞增生综合征是一种淋巴细胞凋亡紊乱。尽管信号转导胞内死亡结构域突变的 FAS 分子表现出对 FAS 介导的凋亡的显性负干扰，但导致自身免疫性淋巴细胞增生综合征的非死亡结构域 FAS 突变的病理机制尚不清楚。
我们对 39 名患有非死亡结构域自身免疫性淋巴细胞增生综合征的患者进行了 RNA 稳定性、蛋白表达、配体结合以及通过抗 FAS 抗体或 FAS 配体传递凋亡信号的能力的检测。在突变阳性的家族成员中建立了突变类型与疾病外显率之间的相关性。
外显子 7 之前的移码突变或转录终止突变导致信使 RNA 单倍体不足，而氨基末端信号序列突变和某些细胞内截断阻止了 FAS 的细胞表面定位。所有这些都导致 FAS 定位减少、无法结合 FAS 配体以及减少 FAS 配体诱导的凋亡。细胞外错义突变和框内缺失表达了有缺陷的 FAS 蛋白，无法结合 FAS 配体，并表现出对 FAS 介导的凋亡的显性负干扰。与死亡结构域突变相比，具有单倍体不足或细胞外突变的突变阳性亲属具有较低的自身免疫性淋巴细胞增生综合征临床表型外显率。
我们已经确定了非死亡结构域 FAS 突变导致淋巴细胞凋亡减少的分子机制，建立了自身免疫性淋巴细胞增生综合征患者突变阳性亲属之间的基因型-表型相关性的层次结构，并证明 FAS 单倍体不足可导致自身免疫性淋巴细胞增生综合征。
