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，但已有报道称Hermansky-Pudlak综合征(HPS)患者的肺纤维化风险与遗传异常显著相关。HPS是一种常染色体隐性遗传病，以眼皮肤白化、溶酶体脂褐素蓄积和出血倾向三联征为特征。HPS是一种罕见的疾病，但常见于波多黎各和瑞士阿尔卑斯山。据报道，日本已有近100名HPS患者。波多黎各和日本的大多数HPS患者会使肺纤维化复杂化，直到第五个十年才会死亡，但在瑞士不会。在本研究中，我们克隆了HPS相关基因HPS-1，全长30.5kb，有20个外显子。目前已发现HPS-1基因有6种以上的异常损伤。HPS-1蛋白在蛋白质转运中的作用已被提出。外显子15是波多黎各最常见的HPS-1基因异常，外显子15的16个碱基重复表示肺纤维化的风险更高。日本HPS合并肺纤维化患者存在外显子15基因多态性，C到C点突变导致Pro49lArg替换。与其他几种肺部疾病和正常人(P&lt；0.001)相比，IPF(52%)也观察到该基因多态的显著积累。此外，在两种肺纤维化、合并结缔组织病的肺纤维化(11%，CTD-IP)和特发性肺纤维化(P&lt；100)中，该基因多态性的存在方式也不同。IPF和CTD-IP遗传背景的差异可能与两组肺纤维化的发病机制不同以及对治疗的反应不同有关。提示HPS-1基因Pro49lArg突变可能是肺纤维化不同发病机制的候选致病因子。

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.