Clinical and cellular characterisation of Hermansky-Pudlak syndrome type 6.
Clinical and cellular characterisation of Hermansky-Pudlak syndrome type 6.
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DOI：
10.1136/jmg.2008.065961
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发表时间：
2009-12
影响因子：
4
通讯作者：
Gahl WA
中科院分区：
文献类型：
--
作者：
Huizing M;Pederson B;Hess RA;Griffin A;Helip-Wooley A;Westbroek W;Dorward H;O'Brien KJ;Golas G;Tsilou E;White JG;Gahl WA
在过去的十年中，Hermansky-Pudlak综合征（HPS）的出现，为细胞生物学家研究溶酶体相关细胞器（LRO）的生物发生提供了指导。在八种人类HPS亚型中，只有亚型1至5得到了很好的描述。在这里，我们仔细描述了HPS-6亚型，引起的缺陷HPS 6，溶酶体相关的细胞器复合物-2（BLOC-2）的生物发生的亚基。对我们未分类的HPS患者组的DNA进行HPS 6基因突变分析。然后仔细确定HPS 6突变患者的临床表型，并将其培养的真皮黑素细胞用于细胞免疫荧光研究。分子生物学研究表明，在单外显子HPS 6基因中存在多种突变，包括移码、错义和无义突变以及跨越整个HPS 6基因的~20-kb缺失。细胞研究表明，黑素生成蛋白酪氨酸酶和酪氨酸酶相关蛋白1未能有效地传递到HPS-6患者的黑素体，解释了他们的色素减退。临床研究表明，HPS-6患者表现出眼皮肤白化病和出血素质。重要的是，肉芽肿性结肠炎和肺纤维化，使人衰弱的特征存在于HPS亚型1和4中，在我们的HPS-6患者中未检测到。总之，HPS-6亚型类似于其他BLOC-2缺陷亚型（即，HPS-3和HPS-5）的分子、细胞和临床表现。这些发现不仅对于为新诊断的HPS-6患者提供预后很重要，而且对于进一步阐明HPS在LRO生物发生中的功能也很重要。
In the last decade, Hermansky-Pudlak syndrome (HPS) has arisen as an instructive disorder for cell biologists to study the biogenesis of lysosome-related organelles (LROs). Of the eight human HPS subtypes, only subtypes 1 through 5 are well described. Here, we carefully characterize the HPS-6 subtype, caused by defects in HPS6, a subunit of the biogenesis of lysosome-related organelles complex-2 (BLOC-2). Mutation analysis for the HPS6 gene was performed on DNA from our group of unclassified HPS patients. The clinical phenotype of patients with HPS6 mutations was then carefully ascertained, and their cultured dermal melanocytes were employed for cellular immunofluorescence studies. Molecular studies showed a variety of mutations in the single-exon HPS6 gene, including frame shift, missense, and nonsense mutations as well as a ~20-kb deletion spanning the entire HPS6 gene. Cellular studies revealed that the melanogenic proteins tyrosinase and tyrosinase-related protein 1 failed to be efficiently delivered to the melanosomes of HPS-6 patients, explaining their hypopigmentation. Clinical studies indicated that HPS-6 patients exhibit oculocutaneous albinism and a bleeding diathesis. Importantly, granulomatous colitis and pulmonary fibrosis, debilitating features present in HPS subtypes 1 and 4, were not detected in our HPS-6 patients. In sum, the HPS-6 subtype resembles other BLOC-2 defective subtypes (i.e., HPS-3 and HPS-5) in its molecular, cellular and clinical findings. These findings are not only important for providing a prognosis to newly diagnosed HPS-6 patients, but also for further elucidation of HPS function in the biogenesis of LROs.
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影响因子：
4.8
作者：
Starcevic, M;Dell'Angelica, EC
通讯作者：
Dell'Angelica, EC
影响因子：
16
作者：
Dell'Angelica, EC;Shotelersuk, V;Bonifacino, JS
通讯作者：
Bonifacino, JS
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4.8
作者：
Martina, JA;Moriyama, K;Bonifacino, JS
通讯作者：
Bonifacino, JS
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作者：
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通讯作者：
Marks, Michael S.
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6.5
作者：
Helip-Wooley, Amanda;Westbroek, Wendy;Gahl, William A.
通讯作者：
Gahl, William A.