Document Detail


A single amino acid change, A91V, leads to conformational changes that can impair processing to the active form of perforin.
MedLine Citation:
PMID:  15741215     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-03-01
Journal Detail:
Title:  Blood     Volume:  106     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-07-21     Completed Date:  2005-09-21     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  932-7     Citation Subset:  AIM; IM    
Affiliation:
Sir William Dunn School of Pathology, South Parks Rd, Oxford OX1 3RE, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
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:
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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