| A single amino acid change, A91V, leads to conformational changes that can impair processing to the active form of perforin. | |
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MedLine Citation:
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PMID: 15741215 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mutations in the perforin gene have been found in patients with hemophagocytic lymphohistiocytosis (HLH), a rare autosomal recessive disease. We describe a patient expressing perforin with amino acid changes A91V and W374X. The ability of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to lyse target cells is greatly reduced. Here we demonstrate that perforin from this patient is not recognized using an antibody raised against native perforin (deltaG9), but is readily detected using an antibody raised against a peptide epitope (2d4), suggesting that the epitope recognized by deltaG9 is destroyed by the change at A91V. Immunoblotting reveals no protein corresponding to the truncated transcript encoded by W374X, revealing that only perforin with the A91V change is expressed in CTLs from the patient. Patient CTLs show bands corresponding to the immature and intermediate forms of perforin, but the mature active form of perforin is absent or barely detectable. The conformational changes and impaired cleavage of A91V perforin are likely to explain the reduced cytotoxicity in CTLs and NK cells from this patient and are likely to contribute to the pathogenesis of HLH. |
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Authors:
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Christina Trambas; Federico Gallo; Daniela Pende; Stefania Marcenaro; Lorenzo Moretta; Carmela De Fusco; Alessandra Santoro; Luigi Notarangelo; Maurizio Arico; Gillian M Griffiths |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2005-03-01 |
Journal Detail:
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Title: Blood Volume: 106 ISSN: 0006-4971 ISO Abbreviation: Blood Publication Date: 2005 Aug |
Date Detail:
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Created Date: 2005-07-21 Completed Date: 2005-09-21 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 932-7 Citation Subset: AIM; IM |
Affiliation:
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Sir William Dunn School of Pathology, South Parks Rd, Oxford OX1 3RE, United Kingdom. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Child, Preschool Cytotoxicity, Immunologic / genetics Epitopes / genetics Female Histiocytosis, Non-Langerhans-Cell / etiology, genetics Humans Killer Cells, Natural / immunology Membrane Glycoproteins / chemistry*, genetics*, metabolism Mutation, Missense* Perforin Pore Forming Cytotoxic Proteins Protein Conformation Protein Processing, Post-Translational* T-Lymphocytes, Cytotoxic / immunology |
| Chemical | |
Reg. No./Substance:
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0/Epitopes; 0/Membrane Glycoproteins; 0/Pore Forming Cytotoxic Proteins; 126465-35-8/Perforin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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