Department of Immunology, University Hospital of Son Espases, Palma de Mallorca, Spain.
Hum Immunol. 2013 Jan;74(1):14-7. doi: 10.1016/j.humimm.2012.10.011. Epub 2012 Oct 13.
Perforin (PRF1) gene mutations have been associated with Familial Hemophagocytic Lymphohistiocytosis type 2 (FHL2). Substitution p.A91V (c.272C>T) in exon 2 was first described as a neutral polymorphism. Nonetheless, recent clinical evidence and functional assays, suggest a potential pathogenic role for p.A91V, especially in compound heterozygous individuals. Moreover, p.A91V homozygosity has been linked to various pathological states including FHL and lymphocytic leukaemias. In the present report we evaluated the impact of this mutation in a compound heterozygous A91V/G149S 31 year-old asymptomatic female. Functional assays revealed low perforin expression levels, as well as an impaired NK cell-mediated cytotoxicity, partially reconstituted after incubation with IL-2. These results support that p.A91V mutation, associated to another mutated PRF1 allele, may potentially predispose seemingly healthy carriers to suffer a milder FHL2 clinical phenotype, including later onset of the disease. Thus, clinical monitoring of p.A91V carrier individuals bearing another mutation in PRF1 is warranted.
穿孔素 (PRF1) 基因突变与家族性噬血细胞性淋巴组织细胞增生症 2 型 (FHL2) 有关。第 2 外显子中的替代 p.A91V (c.272C>T) 最初被描述为中性多态性。然而，最近的临床证据和功能分析表明，p.A91V 可能具有潜在的致病性作用，尤其是在复合杂合子个体中。此外，p.A91V 纯合子与包括 FHL 和淋巴细胞白血病在内的各种病理状态有关。在本报告中，我们评估了该突变在一名 31 岁无症状的复合杂合子 A91V/G149S 女性中的影响。功能分析显示穿孔素表达水平较低，以及 NK 细胞介导的细胞毒性受损，在用 IL-2 孵育后部分得到重建。这些结果表明，p.A91V 突变与另一个突变的 PRF1 等位基因相关，可能使看似健康的携带者易患更轻微的 FHL2 临床表型，包括疾病的发病较晚。因此，需要对携带 PRF1 另一个突变的 p.A91V 携带者进行临床监测。
