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

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

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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10875-019-00731-3) contains supplementary material, which is available to authorized users.