Division of Pediatric Stem Cell Transplantation and Immunology in the Department of Pediatric Hematology and Oncology, University Medical Center Eppendorf, Hamburg, Germany.
Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Blood Adv. 2023 Apr 25;7(8):1531-1535. doi: 10.1182/bloodadvances.2022008195.
Most hereditary forms of hemophagocytic lymphohistiocytosis (HLH) are caused by defects of cytotoxicity, including the vesicle trafficking disorder Griscelli syndrome type 2 (GS2, RAB27A deficiency). Deficiency of the mitogen-activated protein kinase activating death domain protein (MADD) results in a protean syndrome with neurological and endocrinological involvement. MADD acts as a guanine nucleotide exchange factor for small guanosine triphosphatases, including RAB27A. A homozygous splice site mutation in MADD was identified in a female infant with syndromic features, secretory diarrhea, and features of HLH. Aberrant splicing caused by this mutation leads to an in-frame deletion of 30 base pairs and favors other aberrant variants. Patient natural killer (NK) cells and cytotoxic T cells showed a severe degranulation defect leading to absent perforin-mediated cytotoxicity. Platelets displayed defective adenosine triphosphate secretion, similar to that in GS2. To prove causality, we introduced a CRISPR/Cas9-based MADD knockout in the NK cell line NK-92mi. MADD-deficient NK-92mi cells showed a degranulation defect and impaired cytotoxicity similar to that of the patient. The defect of cytotoxicity was confirmed in another patient with MADD deficiency. In conclusion, RAB27A-interacting MADD is involved in vesicle release by cytotoxic cells and platelets. MADD deficiency causes a degranulation defect and represents a novel disease predisposing to an HLH phenotype.
大多数遗传性噬血细胞性淋巴组织细胞增生症（HLH）是由细胞毒性缺陷引起的，包括囊泡运输障碍性格里塞利综合征 2 型（GS2，RAB27A 缺乏）。丝裂原激活的蛋白激酶激活死亡结构域蛋白（MADD）的缺乏导致具有神经和内分泌受累的多系统表现综合征。MADD 作为小 GTP 酶（包括 RAB27A）的鸟嘌呤核苷酸交换因子发挥作用。在一名有综合征特征、分泌性腹泻和 HLH 特征的女性婴儿中发现了 MADD 的纯合剪接位点突变。该突变导致 30 个碱基对的框内缺失，并有利于其他异常变异，从而导致异常剪接。患者自然杀伤（NK）细胞和细胞毒性 T 细胞表现出严重的脱颗粒缺陷，导致穿孔素介导的细胞毒性缺失。血小板显示出缺陷的三磷酸腺苷分泌，类似于 GS2。为了证明因果关系，我们在 NK 细胞系 NK-92mi 中引入了基于 CRISPR/Cas9 的 MADD 敲除。MADD 缺陷型 NK-92mi 细胞表现出脱颗粒缺陷和细胞毒性受损，类似于患者的情况。另一名 MADD 缺乏的患者也证实了细胞毒性缺陷。总之，与 RAB27A 相互作用的 MADD 参与细胞毒性细胞和血小板的囊泡释放。MADD 缺乏导致脱颗粒缺陷，并代表一种新的疾病易感性，导致 HLH 表型。
