Zhang Kejian, Chandrakasan Shanmuganathan, Chapman Heather, Valencia C Alexander, Husami Ammar, Kissell Diane, Johnson Judith A, Filipovich Alexandra H
Division of Human Genetics.
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, and.
Blood. 2014 Aug 21;124(8):1331-4. doi: 10.1182/blood-2014-05-573105. Epub 2014 Jun 10.
Several molecules (LYST, AP3, RAB27A, STX11, STXBP2, MUNC13-4, and PRF1) have been associated with the function of cytotoxic lymphocytes. Biallelic defects in all of these molecules have been associated with familial hemophagocytic lymphohistiocytosis (FHL). We retrospectively reviewed the genetic and immunology test results from 2701 patients with a clinically suspected diagnosis of hemophagocytic lymphohistiocytosis and found 28 patients with single heterozygous mutations in 2 FHL-associated genes. Of these patients, 21 had mutations within PRF1 and a degranulation gene, and 7 were found to have mutations within 2 genes involved in the degranulation pathway. In patients with combination defects involving 2 genes in the degranulation pathway, CD107a degranulation was decreased, comparable to patients with biallelic mutations in one of the genes in the degranulation pathway. This suggests a potential digenic mode of inheritance of FHL as a result of a synergistic function effect within genes involved in cytotoxic lymphocyte degranulation.
几种分子（LYST、AP3、RAB27A、STX11、STXBP2、MUNC13 - 4和PRF1）与细胞毒性淋巴细胞的功能有关。所有这些分子的双等位基因缺陷都与家族性噬血细胞性淋巴组织细胞增生症（FHL）有关。我们回顾性地分析了2701例临床疑似噬血细胞性淋巴组织细胞增生症患者的基因和免疫学检测结果，发现28例患者在2个与FHL相关的基因中存在单杂合突变。在这些患者中，21例在PRF1和一个脱颗粒基因内有突变，7例在参与脱颗粒途径的2个基因内有突变。在脱颗粒途径中涉及2个基因的联合缺陷患者中，CD107a脱颗粒减少，这与脱颗粒途径中一个基因存在双等位基因突变的患者相当。这表明由于细胞毒性淋巴细胞脱颗粒相关基因内的协同功能效应，FHL可能存在潜在的双基因遗传模式。
