title: Novel perforin mutation in a patient with hemophagocytic lymphohistiocytosis and CD45 abnormal splicing.
abstract: Hemophagocytic lymphohistiocytosis (HLH) composes a group of rare heterogenous disorders characterized by uncontrolled accumulation and infiltration of activated T lymphocytes and macrophages. Cytotoxic T and natural killer cell activity is significantly reduced or absent in these patients. Mutations in the important mediator of lymphocyte cytotoxicity perforin were identified in a number of HLH individuals. Here we report a novel missense mutation thr435met in the conserved Ca(2+) binding domain of perforin in a patient with HLH. Prediction of the 3-dimensional structure of the thr435met perforin mutant using comparative molecular modeling indicates that the protein's ability to bind Ca(2+), and therefore its cytolytic function, would be strongly compromised. In addition, this patient exhibited abnormal CD45 splicing caused by a C77G mutation in the gene encoding CD45 (PTPRC). Our findings suggest a combined role for perforin mutation and abnormal CD45 splicing as significant contributory factors in the pathogenesis of HLH.
authors.affiliation: The Edward Jenner Institute for Vaccine Research, Compton, Berkshire RG20 7NN, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: McCormick
authors.forename: Darren R
authors.initials: DR
authors.lastname: Flower
authors.forename: Stephan
authors.initials: S
authors.lastname: Strobel
authors.forename: Diana L
authors.initials: DL
authors.lastname: Wallace
authors.forename: Peter C L
authors.initials: PC
authors.lastname: Beverley
authors.forename: Elma Z
authors.initials: EZ
authors.lastname: Tchilian
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D015616:Histiocytosis, Non-Langerhans-Cell / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D017493:Leukocyte Common Antigens / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D017434:Protein Structure, Tertiary / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D004247:DNA; D017493:Leukocyte Common Antigens