Improper trafficking of melanocyte-specific proteins in Hermansky-Pudlak syndrome type-5

被引:33
作者
Helip-Wooley, Amanda
Westbroek, Wendy
Dorward, Heidi M.
Koshoffer, Amy
Huizing, Marjan
Boissy, Raymond E.
Gahl, William A.
机构
[1] NHGRI, NIH, Med Genet Branch, Sect Human Biochem Genet, Bethesda, MD 20892 USA
[2] Univ Cincinnati, Coll Med, Dept Dermatol, Cincinnati, OH USA
关键词
D O I
10.1038/sj.jid.5700737
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
Hermansky-Pudlak syndrome (HPS) is a disorder of lysosome-related organelle biogenesis resulting in melanosome dysfunction and absent platelet dense bodies. HPS patients have oculocutaneous albinism, bruising, and bleeding. HPS-5 results from deficiency of the HPS5 protein, a component of the biogenesis of lysosome-related organelles complex-2 (BLOC-2). HPS5 has an unknown function and lacks homology to known proteins. We performed ultrastructural studies of HPS-5 melanocytes revealing predominantly early-stage melanosomes with many small 3,4(OH)(2)-phenylalanine-positive vesicles throughout the cell body and dendrites. These findings resemble the distinct ultrastructural features of HPS-3 melanocytes; HPS3 is also a BLOC-2 component. Immunofluorescence and immunoEM studies showed decreased TYRP1 labeling in the dendrites of HPS-5 melanocytes, and the overall abundance of TYRP1 was reduced. No substantial differences were observed in the distribution or abundance of Pmel17 in HPS-5 melanocytes. In normal melanocytes, endogenous tyrosinase colocalized with Pmel17 and TYRP1 in the perinuclear area and dendritic tips; this was much reduced in HPS-5 melanocytes, particularly in the tips. We conclude that early stage melanosome formation and Pmel17 trafficking are preserved in HPS5-deficient cells. Tyrosinase and TYRP1 are mistrafficked, however, and fail to be efficiently delivered to melanosomes of HPS-5 melanocytes.
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页码:1471 / 1478
页数:8
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