Willenbring Robin C, Ikeda Yasuhiro, Pease Larry R, Johnson Aaron J
Mayo Clinic Graduate School of Biomedical Sciences, College of Medicine, Mayo Clinic, Rochester, MN, USA.
Department of Immunology, Mayo Clinic, Rochester, MN, USA.
Mol Genet Genomic Med. 2018 Jan;6(1):44-55. doi: 10.1002/mgg3.344. Epub 2017 Dec 7.
Deleterious mutations in PRF1 result in lethal, childhood disease, familial hemophagocytic lymphohistiocytosis type 2 (FHL 2). However, not all mutations in PRF1 are deleterious and result in FHL 2. Currently, these nondeleterious mutations are being investigated in the onset of numerous disorders, such as lymphomas and diabetes. Yet, there is still an overwhelmingly large amount of PRF1 mutations that are not associated with disease.
We conducted a post hoc analysis of the PRF1 mutations in the coding region using the recently published Exome Aggregation Consortium genomes, Leiden Open Variation Database, NCBI SNP database, and primary literature to better understand PRF1 variation in the human population.
This study catalogs 460 PRF1 mutations in the coding region, and demonstrates PRF1 is more variant then previously predicted. We identify key PRF1 mutations with high allelic frequency and are only found in certain populations. Additionally, we define PRF1 SNVs are geographically distributed.
This study concludes with a novel hypothesis that nondeleterious mutation in PRF1, which decreases perforin expression and/or activity, may be an example of selective advantage in the context of environmental stressors prevalent near the equator. Our studies illustrate how perforin deficiency can be protective from injuries resulting in blood-brain barrier (BBB) disruption.
PRF1基因中的有害突变会导致致命的儿童疾病——2型家族性噬血细胞性淋巴组织细胞增生症（FHL 2）。然而，并非PRF1基因的所有突变都是有害的并导致FHL 2。目前，正在对这些非有害突变在多种疾病（如淋巴瘤和糖尿病）的发病过程中的作用进行研究。然而，仍有大量PRF1基因突变与疾病无关。
我们利用最近公布的外显子聚合联盟基因组、莱顿开放变异数据库、NCBI单核苷酸多态性数据库以及原始文献，对编码区的PRF1基因突变进行了事后分析，以更好地了解人类群体中PRF1基因的变异情况。
本研究对编码区的460个PRF1基因突变进行了编目，并证明PRF1基因的变异比先前预测的更多。我们鉴定出了具有高等位基因频率且仅在特定人群中发现的关键PRF1基因突变。此外，我们确定PRF1单核苷酸变异具有地理分布特征。
本研究得出了一个新的假设，即PRF1基因中的非有害突变会降低穿孔素的表达和/或活性，这可能是在赤道附近普遍存在的环境应激因素背景下的一种选择性优势的例子。我们的研究说明了穿孔素缺乏如何能够保护机体免受导致血脑屏障（BBB）破坏的损伤。
