Entry

Familial Cold Autoinflammatory Syndrome 3

In affected members of 3 unrelated families with familial cold autoinflammatory syndrome-3 (FCAS3; 614468), also known as PLCG2-associated antibody deficiency and immune dysregulation (PLAID), Ombrello et al. (2012) identified 3 different heterozygous intragenic deletions in the PLCG2 gene (600220.0001-600220.0003). The mutations were found by linkage analysis followed by candidate gene sequencing. Five of the 6 deletion breakpoints occurred within repetitive elements. Each of the 3 deletions involved the C-terminal Src-homology-2 (cSH2) domain, which is autoinhibitory and normally prevents constitutive enzymatic function. Transfection of COS-7 cells with PLCG2 constructs lacking the full domain, a deletion of exon 19, or a deletion of exons 20-22 resulted in increased basal and Rac-activated phospholipase activity compared to wildtype. Despite this gain of function, distal signaling and PLCG2-dependent functions were decreased in patient immune cells at physiologic temperatures. The paradoxical loss of downstream function may have resulted from chronic signaling with negative feedback. Patient B cells and natural killer cells both showed defective calcium flux in response to receptor activation on their cell surfaces. However, patient B cells showed increased calcium levels and increased activation with decreasing temperature, whereas control cells did not. Transfection of mutant PLCG2 into mast cells led to spontaneous degranulation at 20 degrees Celsius, which was not seen in controls. The findings indicated that defective receptor signaling in mutant B cells was temperature-dependent and caused abnormal activation and class-switching, resulting in antibody deficiency and impaired central tolerance. The increased activation of mast cells at subphysiologic temperatures was responsible for the cold urticaria.

Autoinflammation, Antibody Deficiency, and Immune Dysregulation

In a father and daughter with autoinflammation, antibody deficiency, and immune dysregulation (APLAID; 614878), Zhou et al. (2012) identified a heterozygous missense mutation in the PLCG2 gene (S707Y; 600220.0004). The mutation was identified by exome sequencing and was demonstrated to result in a gain of function with increased intracellular calcium flux through the IP3 signaling pathway. The disorder was characterized by recurrent blistering skin lesions with a dense inflammatory infiltrate and variable involvement of other tissues, including joints, eyes, and gastrointestinal tract. The patients had a mild humoral immune deficiency associated with recurrent sinopulmonary infections, but no evidence of circulating autoantibodies. Zhou et al. (2012) noted that APLAID was a distinct disorder from PLAID, which they had described earlier (Ombrello et al., 2012), although both disorders shared impaired humoral immune function. In APLAID, the S707Y mutation enhances PLCG2 activation at physiologic temperatures, which the authors speculated may result from the creation of an extra phosphorylation site and compromised autoinhibition leading to a slight increase in basal enzymatic activity that is not sufficient for triggering negative feedback.

In an 11-year-old girl with APLAID, Neves et al. (2018) identified a de novo heterozygous missense mutation in the PLCG2 gene (L848P; 600220.0005). The mutation was identified by exome sequencing and confirmed by Sanger sequencing.