A Germline Mutation in the C2 Domain of PLCγ2 Associated with Gain-of-Function Expands the Phenotype for PLCG2-Related Diseases.

Autor: Novice T; University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA., Kariminia A; Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, Canada., Del Bel KL; Department of Pediatrics, BC Children's Hospital Research Institute, Vancouver, Canada., Lu H; Department of Pediatrics, BC Children's Hospital Research Institute, Vancouver, Canada., Sharma M; Department of Pediatrics, BC Children's Hospital Research Institute, Vancouver, Canada., Lim CJ; Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, Canada., Read J; Department of Pediatrics, Mott Children's Hospital, University of Michigan, Ann Arbor, MI, USA., Lugt MV; Division of Pediatric Hematology/Oncology, Department of Pediatrics, Mott Children's Hospital, University of Michigan, Ann Arbor, MI, USA., Hannibal MC; Division of Pediatric Genetics, Metabolism & Genomic Medicine, Mott Children's Hospital, University of Michigan, Ann Arbor, MI, USA., O'Dwyer D; Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA., Hosler M; Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, MI, USA., Scharnitz T; Department of Dermatology, University of Michigan, Ann Arbor, MI, USA., Rizzo JM; Department of Dermatology, University of Michigan, Ann Arbor, MI, USA., Zacur J; Department of Dermatology, University of Michigan, Ann Arbor, MI, USA., Priatel J; Department of Pediatrics, BC Children's Hospital Research Institute, Vancouver, Canada., Abdossamadi S; Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, Canada., Bohm A; Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, Canada., Junker A; Division of Clinical Immunology & Allergy, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada., Turvey SE; Division of Clinical Immunology & Allergy, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada., Schultz KR; Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, Canada.; Division of Pediatric Hematology/Oncology and Bone Marrow Transplant, Department of Pediatrics, BC Children's Hospital, University of British Columbia, 4480 Oak Street, Vancouver, Canada., Rozmus J; Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, Canada. jrozmus@cw.bc.ca.; Division of Pediatric Hematology/Oncology and Bone Marrow Transplant, Department of Pediatrics, BC Children's Hospital, University of British Columbia, 4480 Oak Street, Vancouver, Canada. jrozmus@cw.bc.ca.
Jazyk: angličtina
Zdroj: Journal of clinical immunology [J Clin Immunol] 2020 Feb; Vol. 40 (2), pp. 267-276. Date of Electronic Publication: 2019 Dec 19.
DOI: 10.1007/s10875-019-00731-3
Abstrakt: We report three new cases of a germline heterozygous gain-of-function missense (p.(Met1141Lys)) mutation in the C2 domain of phospholipase C gamma 2 (PLCG2) associated with symptoms consistent with previously described auto-inflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome and pediatric common variable immunodeficiency (CVID). Functional evaluation showed platelet hyper-reactivity, increased B cell receptor-triggered calcium influx and ERK phosphorylation. Expression of the altered p.(Met1141Lys) variant in a PLCγ2-knockout DT40 cell line showed clearly enhanced BCR-triggered influx of external calcium when compared to control-transfected cells. Our results further expand the molecular basis of pediatric CVID and phenotypic spectrum of PLCγ2-related defects.
Databáze: MEDLINE