A Hypermorphic Missense Mutation in PLCG2, Encoding Phospholipase C gamma 2, Causes a Dominantly Inherited Autoinflammatory Disease with Immunodeficiency

作者：Zhou Qing; Lee Geun Shik; Brady Jillian; Datta Shrimati; Katan Matilda; Sheikh Afzal; Martins Marta S; Bunney Tom D; Santich Brian H; Moir Susan; Kuhns Douglas B; Priel Debra A Long; Ombrello Amanda; Stone Deborah; Ombrello Michael J; Khan Javed; Milner Joshua D; Kastner Daniel L; Aksentijevich Ivona^*

来源：American Journal of Human Genetics, 2012, 91(4): 713-720.

DOI：10.1016/j.ajhg.2012.08.006

Whole-exome sequencing was performed in a family affected by dominantly inherited inflammatory disease characterized by recurrent blistering skin lesions, bronchiolitis, arthralgia, ocular inflammation, enterocolitis, absence of autoantibodies, and mild immunodeficiency. Exome data from three samples, including the affected father and daughter and unaffected mother, were filtered for the exclusion of reported variants, along with benign variants, as determined by PolyPhen-2. A total of eight transcripts were identified as possible candidate genes. We confirmed a variant, c.2120C%26gt;A (p.Ser707Tyr), within PLCG2 as the only de novo variant that was present in two affected family members and not present in four unaffected members. PLCG2 encodes phospholipase C gamma 2 (PLC gamma 2), an enzyme with a critical regulatory role in various immune and inflammatory pathways. The p.Ser707Tyr substitution is located in an autoinhibitory SH2 domain that is crucial for PLC gamma 2 activation. Overexpression of the altered p.Ser707Tyr protein and ex vivo experiments using affected individuals%26apos; leukocytes showed clearly enhanced PLC gamma 2 activity, suggesting increased intracellular signaling in the PLC gamma 2-mediated pathway. Recently, our laboratory identified in individuals with cold-induced urticaria and immune dysregulation PLCG2 exon-skipping mutations resulting in protein products with constitutive phospholipase activity but with reduced intracellular signaling at physiological temperatures. In contrast, the p.Ser707Tyr substitution in PLC gamma 2 causes a distinct inflammatory phenotype that is not provoked by cold temperatures and that has different end-organ involvement and increased intracellular signaling at physiological temperatures. Our results highlight the utility of exome-sequencing technology in finding causal mutations in nuclear families with dominantly inherited traits otherwise intractable by linkage analysis.

• 出版日期2012-10-5