The Hermansky-Pudlak syndrome 1 (HPS1) and HPS2 genes independently contribute to the production and function of platelet dense granules, melanosomes, and lysosomes
The Hermansky-Pudlak syndrome 1 (HPS1) and HPS2 genes independently contribute to the production and function of platelet dense granules, melanosomes, and lysosomes
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DOI：
10.1182/blood.v99.5.1651.h8001651_1651_1658
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发表时间：
2002-03-01
期刊：
影响因子：
20.3
通讯作者：
Swank, RT
中科院分区：
文献类型：
--
作者：
Feng, LJ;Novak, EK;Swank, RT
Hermansky-Pudiak综合征（HPS）是一种遗传性出血性疾病，影响相关的亚细胞器血小板致密颗粒、溶酶体和黑素体。小鼠的HIPS、白耳和珍珠基因与人类HPS 1和HPS 2（ADTB 3A）基因同源，分别编码一种功能未知的新蛋白和AP-3接头复合物的β（3）A亚基。为了测试这些基因在细胞内细胞器的产生和功能中的体内相互作用，通过适当的育种产生了2种突变基因的双纯合小鼠。在黑素体生产的2个基因之间的合作是显而易见的，增加色素减退的外套，以及戏剧性的数量和质量的变化的黑素体的视网膜色素上皮细胞和脉络膜的双突变小鼠。溶酶体和血小板致密颗粒异常，包括肾脏溶酶体酶分泌不足和血小板致密颗粒的5-羟色胺浓度的抑郁症同样更严重的双比单突变体。此外，双突变小鼠肺中溶酶体酶浓度显著增加。2个基因之间的相互作用是特定的，对细胞器的影响仅限于黑素体，溶酶体和血小板致密颗粒。总之，证据表明这2个HPS基因在整个生物体水平上很大程度上独立地发挥作用，影响所有3个细胞器的产生和功能。此外，双突变小鼠肺中溶酶体酶水平的增加表明HPS的主要临床问题肺纤维化的原因。最后，双突变HPS小鼠是一个有用的实验室模型，用于分析严重的HPS表型。
Hermansky-Pudiak syndrome (HPS) is an inherited hemorrhagic disease affecting the related subcellular organelles platelet dense granules, lysosomes, and melanosomes. The mouse genes for HIPS, pale ear and pearl, orthologous to the human HPS1 and HPS2 (ADTB3A) genes, encode a novel protein of unknown function and the beta(3)A subunit of the AP-3 adaptor complex, respectively. To test for In vivo interactions between these genes In the production and function of intracellular organelles, mice doubly homozygous for the 2 mutant genes were produced by appropriate breeding. Cooperation between the 2 genes In melanosome production was evident in increased hypopigmentation of the coat together with dramatic quantitative and qualitative alterations of melanosomes of the retinal pigment epithelium and choroid of double mutant mice. Lysosomal and platelet dense granule abnormalities, including hyposecretion of lysosomal enzymes from kidneys and depression of serotonin concentrations of platelet dense granules were likewise more severe in double than single mutants. Also, lysosomal enzyme concentrations were significantly increased In lungs of double mutant mice. Interaction between the 2 genes was specific in that effects on organelles were confined to melanosomes, lysosomes, and platelet dense granules. Together, the evidence indicates these 2 HPS genes function largely independently at the whole organism level to affect the production and function of all 3 organelles. Further, the increased lysosomal enzyme levels in lung of double mutant mice suggest a cause of a major clinical problem of HPS, lung fibrosis. Finally, doubly mutant HPS mice are a useful laboratory model for analysis of severe HPS phenotypes.