Analysis of genetic abnormality in Hermansky-Pudlak syndrome with interstitial pneumonia.

特发性肺纤维化（IPF）的发病机制尚不清楚，但已有研究表明，遗传异常与HPS患者发生肺纤维化的风险显著相关。HPS是一种常染色体隐性遗传病，其特征为眼皮肤白化病、溶酶体脂褐素沉积和出血倾向三联征。HPS是一种罕见的疾病，但经常在波多黎各和瑞士阿尔卑斯山观察到。日本已报告近100例HPS患者。在波多黎各和日本，大多数HPS患者并发肺纤维化并死亡至50岁，但在瑞士没有。本研究克隆了HPS-1基因，全长30.5kb，包含20个外显子。在HPS-1基因中检测到6个以上的异常病变。HPS-1基因外显子15的16个碱基重复是波多黎各最常见的HPS-1基因异常，它代表了肺纤维化的高风险。然而，没有分析的日本UPS患者显示外显子15中的16bp重复。日本HPS肺纤维化患者在第15外显子存在基因多态性，C → C点突变导致Pro49lArg置换。与其他几种肺部疾病和正常人相比，在IPF（52%）中也观察到该基因多态性的显著积累（p <0.0001）。此外，该基因多态性在两种肺纤维化，结缔组织病相关性肺纤维化（11%，CTD-IP）和IPF（p <0.0001）之间存在不同的模式。IPF和CTD-IP的遗传背景差异可能与两组间肺纤维化发病机制的差异以及对治疗反应的差异有关。提示HPS-1基因的Pro49lArg替换可能是肺纤维化的一个潜在的促遗传因子，并可区分不同的肺纤维化机制。

The pathogenesis of idiopathic pulmonary fibrosis (IPF) is still unknown, however, significant correlation of risk of pulmonary fibrosis and genetic abnormality in patients with Hermansky-Pudlak syndrome (HPS) has been reported. HPS is an autosomal recessive disorder characterized by triad of oculocutaneous albinism, lysosomal lipofuscin storage and bleeding tendency. HPS is a rare disease but frequently observed in Puerto Rico and Swiss Alps. Almost 100 HPS patients have been reported in Japan. Most of HPS patients in Puerto Rico and Japan complicate pulmonary fibrosis and die until 5th decade, but not in Swiss. In this study, we have cloned HPS-responsible gene, HPS-1, which expands 30.5kb with 20 exons. More than 6 abnormal lesions in HPS-1 gene has been detected. Putative role of HPS-1 protein on protein trafficking has been proposed.Sixteen bp duplication in exon 15, a most popular HPS-1 gene abnormality in Puerto Rico, represents higher risk of pulmonary fibrosis. However, none of analyzed Japanese UPS patients showed l6bp duplication in exon 15. Japanese HPS patients with pulmonary fibrosis were revealed to have gene polymorphism in exon 15, C to C point mutation resulting Pro49lArg substitution. Significant accumulation of this gene polymorphism was also observed in IPF (52%) in contrast to other several lung diseases and normals (p<O.OOOl). Furthermore, different pattern on the existence of this gene polymorphism between two pulmonary fibrosis, pulmonary fibrosis associated with connective tissue disease (11%, CTD-IP) and IPF (p<0.OOOl) was observed. This difference of genetic background between IPF and CTD-IP might relate to the pathogenetic difference of pulmonary fibrosis as well as different response to the therapy between two groups. This result suggests Pro49lArg substitution in HPS-1 gene might be a putative candidate of progenetic factor for and distinguish different mechanism of pulmonary fibrosis.