2003 Fiscal Year Final Research Report Summary
Molecular genetics of SPINK5
| Project/Area Number |
13470174
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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 |
Dermatology
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| Research Institution | Hyogo College of Medicine (2003)
Mie University (2002)
Kyoto Prefectural University of Medicine (2001) |
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Principal Investigator |
YAMANISHI Kiyofumi Hyogo College of Medicine, Faculty of Medicine, Professor, 医学部, 教授 (10182586)
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| Project Period (FY) |
2001 – 2003
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| Keywords | Ichthyosis / Transglutaminase / Serine protease / Protease inhibitors / Disease Model / Keratinization disorders |
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| Research Abstract |
Netherton syndrome is characterized by ichthyosis, atopy, and trichorrhexis invasinata. The disease gene for the syndrome has been identified to be SPINK5 for a serine protease inhibitor. However, the molecular pathogenesis of the ichthyosis is still unknown. This study is to analyze the role of serine protease systems in keratinization and elucidate the pathogenesis of ichthyosis using mouse models. The mouse SPINK5 gene was isolated from a 129Sv/J mouse genomic DNA library and made a targeting vector. After the homologous recombination in ES cells under the selection with G418, several ES clones with the disrupted SPINK5 gene were cloned. SPINK5 knockout mice were generated using one of those ES clones. However, no substantial abnormal phenotype was found in those knockout mice. On the other hand, transglutaminase 1 knockout mice(TGase1^<-/->) skin grafted onto nude mice developed an ichthyosiform skin phenotype. The gene expression profile of perinatal TGase1^<-/-> skin using a mouse DNA chip revealed that 38 genes are up-regulated and 236 genes are down-regulated in TGase1^<-/-> skin. Of those, BSSP, a gene for a serine protease, is expressed predominantly in brain and skin. Real-time PCR analysis showed that the BSSP gene is over-expressed in perinatal TGase1^<-/-> skin.
Immunohistochemistry using an anti-BSSP antibody revealed that the fully developed icthyosiform skin of TGase1^<-/-> grafted skins are highly positive for BSSP. BSSP may be a target molecule for the formation of the ichthyosiform skin phenotype in keratinization disorders.
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