Mayr Gabriele, Bublitz Maike, Steiert Tim A, Löscher Britt-Sabina, Wittig Michael, ElAbd Hesham, Gassner Christoph, Franke Andre
Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein (UKSH) and Christian-Albrechts-University of Kiel, Kiel, Germany.
Institute of Translational Medicine, Faculty of Medical Sciences, Private University in the Principality of Liechtenstein (UFL), Triesen, Liechtenstein.
Front Immunol. 2024 Dec 6;15:1452637. doi: 10.3389/fimmu.2024.1452637. eCollection 2024.
Kell is one of the most complex blood group systems, with a highly polymorphic genetic background. Extensive allelic variations in the gene affect the encoded erythrocyte surface protein Kell. Genetic variants causing aberrant splicing, premature termination of protein translation, or specific amino acid exchanges lead to a variety of different phenotypes with altered Kell expression levels or changes in the antigenic properties of the Kell protein. Using an structural model of the Kell protein, we analyzed the biophysical and structural context of all full-length Kell variants of known phenotype. The results provided insights regarding the 3D co-localization of antigenic Kell variants and led us to suggest several conformational epitopes on the Kell protein surface. We found a number of correlations between the properties of individual genetic variants in the Kell protein and their respective serological phenotypes, which we used as a search filter to predict potentially new immunogenic Kell variants from an in-house whole exome sequencing dataset of 19,772 exomes. Our analysis workflow and results aid blood group serologists in predicting whether a newly identified Kell genetic variant may result in a specific phenotype.
凯尔血型系统是最复杂的血型系统之一，具有高度多态性的遗传背景。该基因广泛的等位基因变异会影响编码的红细胞表面蛋白凯尔。导致异常剪接、蛋白质翻译提前终止或特定氨基酸交换的基因变异会导致多种不同的表型，表现为凯尔表达水平改变或凯尔蛋白抗原特性变化。利用凯尔蛋白的结构模型，我们分析了所有已知表型的全长凯尔变异体的生物物理和结构背景。研究结果为抗原性凯尔变异体的三维共定位提供了见解，并使我们能够推测凯尔蛋白表面的几个构象表位。我们发现凯尔蛋白中单个基因变异体的特性与其各自的血清学表型之间存在许多相关性，我们将这些相关性用作搜索过滤器，从一个包含19772个外显子组的内部全外显子组测序数据集中预测潜在的新免疫原性凯尔变异体。我们的分析流程和结果有助于血型血清学家预测新鉴定的凯尔基因变异体是否可能导致特定表型。
