Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia 30602, USA.
J Biol Chem. 2010 Sep 3;285(36):28343-52. doi: 10.1074/jbc.M110.109199. Epub 2010 Jul 1.
Accumulating evidence reveals that sole mutations in hENT3 cause a spectrum of human genetic disorders. Among these include H syndrome, characterized by scleroderma, hyperpigmentation, hypertrichosis, hepatomegaly, cardiac abnormalities and musculoskeletal deformities, pigmented hypertrichotic dermatosis with insulin-dependent diabetes syndrome, characterized by autoantibody-negative diabetes mellitus and skin deformities, familial Rosai-Dorfman disease, characterized by short stature, familial histiocytosis and sinus histiocytosis with massive lymphadenopathy (SHML), characterized by severe tissue infiltration of immune cells and swollen lymph nodes. hENT3 spectrum disorders share a common mutation and share overlapping clinical manifestations that display many intriguing resemblances to mitochondrial and lysosomal disorders. Although earlier studies identify hENT3 as a mitochondrial and a lysosomal nucleoside transporter, the precise connections between hENT3 and the pathophysiology of these disorders remain unresolved. In this study, we performed functional and biochemical characterization of these mutations in hENT3. We report severe reductions/losses of hENT3 nucleoside transport functions of hENT3 syndrome mutants. In addition to transport alterations, we provide evidence for possible loss of hENT3 functions in all H and pigmented hypertrichotic dermatosis with insulin-dependent diabetes syndromes due to either mistrafficking or altered stability of mutant hENT3 proteins.
越来越多的证据表明，hENT3 中的单一突变会导致一系列人类遗传疾病。其中包括 H 综合征，其特征为硬皮病、色素沉着过度、多毛症、肝肿大、心脏异常和骨骼肌肉畸形；色素性多毛性皮肤病伴胰岛素依赖型糖尿病综合征，其特征为自身抗体阴性的糖尿病和皮肤畸形；家族性 Rosai-Dorfman 病，其特征为身材矮小；家族性组织细胞增生症和窦组织细胞增生伴巨大淋巴结病（SHML），其特征为免疫细胞严重浸润和淋巴结肿大。hENT3 谱疾病具有共同的突变，且具有重叠的临床表现，与线粒体和溶酶体疾病有许多有趣的相似之处。尽管早期的研究将 hENT3 鉴定为线粒体和溶酶体核苷转运蛋白，但 hENT3 与这些疾病的病理生理学之间的确切联系仍未解决。在本研究中，我们对 hENT3 中的这些突变进行了功能和生化表征。我们报告 hENT3 综合征突变体的 hENT3 核苷转运功能严重降低/丧失。除了转运改变外，我们还提供了证据表明，由于错误运输或突变 hENT3 蛋白的稳定性改变，所有 H 综合征和色素性多毛性皮肤病伴胰岛素依赖型糖尿病综合征的 hENT3 功能可能丧失。
