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

Taylor Novice; Amina Kariminia; Kate L Del Bel; Henry Lu; Mehul Sharma; Chinten J Lim; Jay Read; Mark Vander Lugt; Mark C Hannibal; David O'Dwyer; Mirie Hosler; Thomas Scharnitz; Jason M Rizzo; Jennifer Zacur; John Priatel; Sayeh Abdossamadi; Alexandra Bohm; Anne Junker; Stuart E Turvey; Kirk R Schultz; Jacob Rozmus

doi:10.1007/s10875-019-00731-3

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

J Clin Immunol. 2020 Feb;40(2):267-276. doi: 10.1007/s10875-019-00731-3. Epub 2019 Dec 19.

Authors

Taylor Novice¹, Amina Kariminia², Kate L Del Bel³, Henry Lu³, Mehul Sharma³, Chinten J Lim², Jay Read⁴, Mark Vander Lugt⁵, Mark C Hannibal⁶, David O'Dwyer⁷, Mirie Hosler⁸, Thomas Scharnitz⁹, Jason M Rizzo⁹, Jennifer Zacur⁹, John Priatel³, Sayeh Abdossamadi², Alexandra Bohm², Anne Junker¹⁰, Stuart E Turvey¹⁰, Kirk R Schultz^{2

11}, Jacob Rozmus^{12

13}

Affiliations

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.
³ Department of Pediatrics, BC Children's Hospital Research Institute, Vancouver, 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.
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.
¹² Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, Canada. jrozmus@cw.bc.ca.
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. jrozmus@cw.bc.ca.

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.

Keywords: Germline PLCγ2 mutations; PLCγ2 C2 domain.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Autoimmunity / genetics
B-Lymphocytes / immunology*
Calcium Signaling
Cell Line
Child
Child, Preschool
Common Variable Immunodeficiency / diagnosis*
Female
Germ-Line Mutation / genetics*
Humans
Immunologic Deficiency Syndromes / diagnosis*
Infant
Male
Mutation, Missense / genetics*
Phenotype
Phospholipase C gamma / genetics*
Protein Domains / genetics

Substances

Phospholipase C gamma

Grants and funding

R00 HL139996/HL/NHLBI NIH HHS/United States