Notarangelo Luigi D, Miao Carol H, Ochs Hans D
Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA, USA.
Curr Opin Hematol. 2008 Jan;15(1):30-6. doi: 10.1097/MOH.0b013e3282f30448.
Wiskott-Aldrich syndrome is caused by mutations of the Wiskott-Aldrich syndrome protein gene, which codes for a cytoplasmic protein with multiple functions. This review will focus on recent progress in understanding the molecular basis of Wiskott-Aldrich syndrome and its ramifications for the cure of this lethal disease.
The discovery of the causative gene has revealed a spectrum of clinical phenotypes demonstrating a strong genotype/phenotype correlation. The discovery of unique functional domains of Wiskott-Aldrich syndrome protein has been instrumental in defining mechanisms that control activation of Wiskott-Aldrich syndrome protein. Long-term follow up of patients undergoing hematopoietic stem cell transplantation has led to important modifications of the procedure. Studies of Wiskott-Aldrich syndrome protein-deficient cell lines and wasp-knockout mice have paved the way for possible gene therapy.
Wiskott-Aldrich syndrome protein gene mutations result in four clinical phenotypes: classic Wiskott-Aldrich syndrome and X-linked thrombocytopenia, intermittent thrombocytopenia and neutropenia. Wiskott-Aldrich syndrome protein is a signaling molecule and instrumental for cognate and innate immunity, cell motility and protection against autoimmune disease. The success of hematopoietic stem cell transplantation is related to the recipient's age, donor selection, the conditioning regimen and the extent of reconstitution. Since Wiskott-Aldrich syndrome protein is expressed exclusively in hematopoietic stem cells, and because Wiskott-Aldrich syndrome protein exerts a strong selective pressure, gene therapy is expected to cure the disease.
威斯科特-奥尔德里奇综合征由威斯科特-奥尔德里奇综合征蛋白基因突变引起，该基因编码一种具有多种功能的细胞质蛋白。本综述将聚焦于在理解威斯科特-奥尔德里奇综合征分子基础及其对这种致命疾病治疗影响方面的最新进展。
致病基因的发现揭示了一系列临床表型，显示出很强的基因型/表型相关性。威斯科特-奥尔德里奇综合征蛋白独特功能域的发现有助于确定控制威斯科特-奥尔德里奇综合征蛋白激活的机制。对接受造血干细胞移植患者的长期随访导致了该治疗程序的重要改进。对威斯科特-奥尔德里奇综合征蛋白缺陷细胞系和黄蜂基因敲除小鼠的研究为可能的基因治疗铺平了道路。
威斯科特-奥尔德里奇综合征蛋白基因突变导致四种临床表型：经典威斯科特-奥尔德里奇综合征、X连锁血小板减少症、间歇性血小板减少症和中性粒细胞减少症。威斯科特-奥尔德里奇综合征蛋白是一种信号分子，对同源免疫和固有免疫、细胞运动以及预防自身免疫性疾病至关重要。造血干细胞移植的成功与受者年龄、供体选择、预处理方案和重建程度有关。由于威斯科特-奥尔德里奇综合征蛋白仅在造血干细胞中表达，且由于威斯科特-奥尔德里奇综合征蛋白施加强大的选择压力，基因治疗有望治愈该疾病。
