Background: PRF1 gene mutations are associated with familial hemophagocytic lymphohistiocytosis type 2 (FHL2). Genotype-phenotype analysis, previously hampered by limited number of patients, was performed for the first time by data pooling from 5 large centers worldwide. Patients and methods: Members of the Histiocyte Society were asked to report cases of FHL2 on specific forms. Data were pooled in a common data-based and analysed. Results: The 124 patients had 63 different mutations, including 15 novel: 11 nonsense, 10 frameshift, 38 missense, 4 in-frame deletions. Some mutations were found more frequently: 1122 G>A (W374X), associated with Turkish origin, in 32 patients; 50delT (L17fsX22) associated with Afro(American) origin, in 21; 1090-91delCT (L364fsX), in 7 Japanese patients. Perforin expression was absent at flow-cytometry in 40, reduced in 6, normal in 4 patients. Patients presented at a median age of 3 months (quartiles: 2, 3, and 13 months), always with fever, splenomegaly, and thrombocytopenia. NK activity was absent in 36 (51%), ≤2% in 18 (26%), 3 to ≤5% in 10 (14%), >5% in 4 (6%), "reduced" in 2 (3%) (not reported, n=54). Nonsense mutations were significantly associated with younger age at onset (p<0.001) and absent NK activity (p=0.008). Conclusion: PRF1 mutations are spread over the functional domains. Specific mutations are tightly associated with Turkish, Afro-American, and Japanese ethnic groups. Later onset and residual cytotoxic function are observed in patients with at least one missense mutation.
- Natural killer
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