1998 Fiscal Year Final Research Report Summary
Analysis of genetic abnormality in Hermansky-Pudlak syndrome with interstitial pneumonia.
| Project/Area Number |
08457186
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | Juntendo University School of Medicine |
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Principal Investigator |
TAMURA Naoaki Juntendo Univ, Sch of Med, assist Professor, 医学部, 講師 (10188435)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Hideki Juntendo Univ, Sch of Med, assistant Professor, 医学部, 講師 (90216747)
SETOGUCHI Yasuhiro Juntendo Univ, Sch of Med, Clinical staff, 医学部, 助手 (90206649)
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| Project Period (FY) |
1996 – 1998
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| Keywords | HPS-1 / pulmonary fibrosis / protein trafficking / gene polymorphism / AP-3 |
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| Research Abstract |
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.
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