Horwitz Marshall, Benson Kathleen F, Duan Zhijun, Li Feng-Qian, Person Richard E
Division of Medical Genetics/Department of Medicine, University of Washington School of Medicine, 1705 NE Pacific Street, HSB-K236B, Box 357720 Seattle, WA 98195, USA.
Trends Mol Med. 2004 Apr;10(4):163-70. doi: 10.1016/j.molmed.2004.02.002.
Mutations in ELA2, the gene encoding neutrophil elastase (NE), cause the human diseases cyclic neutropenia (CN) and severe congenital neutropenia (SCN). Numerous mutations are known, but their lack of consistent biochemical effect has proven puzzling. The recent finding that mutation of AP3B1, which encodes the beta subunit of adaptor protein complex 3 (AP3), is the cause of canine CN suggests a model for the molecular basis of hereditary neutropenias, involving the mistrafficking of NE: AP3 recognizes NE as a cargo protein, and their interaction implies that NE is a transmembrane protein. Computerized algorithms predict two NE transmembrane domains. Most CN mutations fall within predicted transmembrane domains and lead to excessive deposition of NE in granules, whereas SCN mutations usually disrupt the AP3 recognition sequence, resulting in excessive transport to the plasma membrane.
编码中性粒细胞弹性蛋白酶（NE）的基因ELA2发生突变，会导致人类疾病周期性中性粒细胞减少症（CN）和严重先天性中性粒细胞减少症（SCN）。已知有许多突变，但它们缺乏一致的生化效应，这一点令人困惑。最近发现，编码衔接蛋白复合物3（AP3）β亚基的AP3B1发生突变是犬类CN的病因，这提示了一种遗传性中性粒细胞减少症分子基础的模型，涉及NE的错误运输：AP3将NE识别为货物蛋白，它们之间的相互作用意味着NE是一种跨膜蛋白。计算机算法预测NE有两个跨膜结构域。大多数CN突变位于预测的跨膜结构域内，导致NE在颗粒中过度沉积，而SCN突变通常会破坏AP3识别序列，导致向质膜的过度运输。
