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

Authors
  • Novice, Taylor1
  • Kariminia, Amina2
  • Del Bel, Kate L3
  • Lu, Henry3
  • Sharma, Mehul3
  • Lim, Chinten J2
  • Read, Jay4
  • Lugt, Mark Vander5
  • Hannibal, Mark C6
  • O'Dwyer, David7
  • Hosler, Mirie8
  • Scharnitz, Thomas9
  • Rizzo, Jason M9
  • Zacur, Jennifer9
  • Priatel, John3
  • Abdossamadi, Sayeh2
  • Bohm, Alexandra2
  • Junker, Anne10
  • Turvey, Stuart E10
  • Schultz, Kirk R2, 11
  • And 1 more
  • 1 University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA.
  • 2 Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, Canada. , (Canada)
  • 3 Department of Pediatrics, BC Children's Hospital Research Institute, Vancouver, Canada. , (Canada)
  • 4 Department of Pediatrics, Mott Children's Hospital, University of Michigan, Ann Arbor, MI, USA.
  • 5 Division of Pediatric Hematology/Oncology, Department of Pediatrics, Mott Children's Hospital, University of Michigan, Ann Arbor, MI, USA.
  • 6 Division of Pediatric Genetics, Metabolism & Genomic Medicine, Mott Children's Hospital, University of Michigan, Ann Arbor, MI, USA.
  • 7 Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 8 Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, MI, USA.
  • 9 Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
  • 10 Division of Clinical Immunology & Allergy, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada. , (Canada)
  • 11 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. , (Canada)
  • 12 Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, Canada. [email protected] , (Canada)
  • 13 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. [email protected] , (Canada)
Type
Published Article
Journal
Journal of Clinical Immunology
Publisher
Springer-Verlag
Publication Date
Feb 01, 2020
Volume
40
Issue
2
Pages
267–276
Identifiers
DOI: 10.1007/s10875-019-00731-3
PMID: 31853824
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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.

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