Journal article

Fatal immune dysregulation due to a gain of glycosylation mutation in lymphocyte perforin

Jenny Chia, Kevin Thia, Amelia J Brennan, Margaret Little, Bronwyn Williams, Jamie A Lopez, Joseph A Trapani, Ilia Voskoboinik

BLOOD | AMER SOC HEMATOLOGY | Published : 2012


Mutations in the perforin gene (PRF1) are a common cause of the fatal immune dysregulation disorder, familial hemophagocytic lymphohistiocytosis (type 2 FHL, FHL2). Here we report a female infant born with biallelic PRF1 mutations: a novel substitution, D49N, and a previously identified in-frame deletion, K285del. We assessed the effects of each mutation on the cytotoxicity of human NK cells in which the expression of endogenous perforin was ablated with miR30-based short hairpin (sh) RNAs. Both mutations were detrimental for function, thereby explaining the clinically severe presentation and rapidly fatal outcome. We demonstrate that D49N exerts its deleterious effect by generating an addit..

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