title: Synergistic defects of different molecules in the cytotoxic pathway lead to clinical familial hemophagocytic lymphohistiocytosis.
abstract: Several molecules (LYST, AP3, RAB27A, STX11, STXBP2, MUNC13-4, and PRF1) have been associated with the function of cytotoxic lymphocytes. Biallelic defects in all of these molecules have been associated with familial hemophagocytic lymphohistiocytosis (FHL). We retrospectively reviewed the genetic and immunology test results from 2701 patients with a clinically suspected diagnosis of hemophagocytic lymphohistiocytosis and found 28 patients with single heterozygous mutations in 2 FHL-associated genes. Of these patients, 21 had mutations within PRF1 and a degranulation gene, and 7 were found to have mutations within 2 genes involved in the degranulation pathway. In patients with combination defects involving 2 genes in the degranulation pathway, CD107a degranulation was decreased, comparable to patients with biallelic mutations in one of the genes in the degranulation pathway. This suggests a potential digenic mode of inheritance of FHL as a result of a synergistic function effect within genes involved in cytotoxic lymphocyte degranulation.
authors.affiliation: Division of Human Genetics.
authors.forename: Kejian
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, and.
authors.forename: Shanmuganathan
authors.initials: S
authors.lastname: Chandrakasan
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Heather
authors.initials: H
authors.lastname: Chapman
authors.affiliation: Division of Human Genetics.
authors.forename: C Alexander
authors.initials: CA
authors.lastname: Valencia
authors.affiliation: Division of Human Genetics.
authors.forename: Ammar
authors.initials: A
authors.lastname: Husami
authors.affiliation: Division of Human Genetics.
authors.forename: Diane
authors.initials: D
authors.lastname: Kissell
authors.affiliation: Division of Human Genetics.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, and.
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Filipovich
mesh_terms: D000293:Adolescent; D000328:Adult; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D004843:Epistasis, Genetic / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D007223:Infant; D008214:Lymphocytes / Q000276:immunology*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000235:genetics / Q000276:immunology; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000276:immunology; D012189:Retrospective Studies
chemical_list: D052118:Lysosomal-Associated Membrane Protein 1; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin