Cellular and molecular defects in a patient with Hermansky-Pudlak syndrome type 5

Hermansky-Pudlak syndrome (HPS) is a heterogeneous group of genetic disorders typically manifesting with tyrosinase-positive oculocutaneous albinism, bleeding diathesis, and pulmonary fibrosis, in some subtypes. Most HPS subtypes are associated with defects in Biogenesis of Lysosome-related Organelle Complexes (BLOCs), which are groups of proteins that function together in the formation and/or trafficking of lysosomal-related endosomal compartments. BLOC-2, for example, consists of the proteins HPS3, HPS5, and HPS6. Here we present an HPS patient with defective BLOC-2 due to a novel intronic mutation in HPS5 that activates a cryptic acceptor splice site. This mutation leads to the insertion of nine nucleotides in-frame and results in a reduced amount of HPS5 at the transcript and protein level. In studies using skin fibroblasts derived from the proband and two other individuals with HPS-5, we found a perinuclear distribution of acidified organelles in patient cells compared to controls. Our results suggest the role of HPS5 in the endo-lysosomal dynamics of skin fibroblasts.赫曼斯基-普德拉克综合征（Hermansky-Pudlak syndrome, HPS）是一组遗传性异质性疾病，多数亚型以酪氨酸酶阳性眼皮肤白化病、出血倾向为典型表现，部分亚型还可并发肺纤维化。大多数HPS亚型与溶酶体相关细胞器复合物生物发生复合体（Biogenesis of Lysosome-related Organelle Complexes, BLOCs）的功能缺陷相关，该类复合体是一组协同参与溶酶体相关内体区室形成与/或转运的蛋白质集合。例如，BLOC-2由HPS3、HPS5及HPS6三种蛋白质构成。本研究报道一例因HPS5基因新型内含子突变激活隐蔽性剪接受体位点，进而导致BLOC-2功能缺陷的HPS患者。该突变使转录本插入9个读码框内核苷酸，并使得转录及蛋白水平的HPS5表达量降低。研究团队利用先证者及另外两例HPS-5型患者的皮肤成纤维细胞开展实验，结果显示与对照组相比，患者细胞内酸化细胞器呈现核周分布特征。本研究结果提示HPS5在皮肤成纤维细胞的内体-溶酶体动态过程中发挥重要作用。