Halacli Sevil Oskay
Division of Pediatric Immunology, Department of Basic Sciences of Pediatrics, Institute of Child's Health, Hacettepe University, Ankara, Turkey.
Immunol Res. 2022 Feb;70(1):56-66. doi: 10.1007/s12026-021-09239-8. Epub 2021 Oct 7.
In the diagnosis of primary immunodeficiencies which are heterogeneous groups of genetic disorders, next-generation sequencing strategies take an important place. Protein expression analyses and some functional studies which are fundamental to determine the pathogenicity of the mutation are also performed to accelerate the diagnosis of PIDs before sequencing. However, protein expressions and functions do not always reflect the genetic and clinical background of the disease even the existence of a pathogenic variant or vice versa. In this study, it was aimed to understand genotype-proteophenotype-clinicophenotype correlation by investigating the effect of mutation types on protein expression, function, and clinical severity in X-linked, autosomal dominant, and autosomal recessive forms of PIDs. It was searched in PubMed and Web of Science without any restrictions on study design and publication time. Totally, 1178 patients with PIDs who have 553 different mutations were investigated from 174 eligible full-text articles. For all mutations, the effect of mutation type on protein expressions and protein functions was analyzed. Furthermore, the most frequent missense and nonsense mutations that were identified in patients with PIDs were evaluated to determine the genotype-clinicophenotype correlation. Protein expressions and functions were changed depending on the mutation type and the affected domain. A significant relationship was observed between protein expression level and clinical severity among all investigated patients. There was also a positive correlation between clinical severity and the affected domains. Mutation types and affected domains should be carefully evaluated with respect to protein expression levels and functional changes during the evaluation of clinico-phenotype.
在原发性免疫缺陷病（一组异质性遗传疾病）的诊断中，新一代测序策略占据重要地位。在测序之前，还会进行蛋白质表达分析和一些功能研究，这些对于确定突变的致病性至关重要，以加速原发性免疫缺陷病的诊断。然而，即使存在致病变异，蛋白质表达和功能也并不总是能反映疾病的遗传和临床背景，反之亦然。在本研究中，旨在通过研究突变类型对X连锁、常染色体显性和常染色体隐性形式的原发性免疫缺陷病的蛋白质表达、功能及临床严重程度的影响，来了解基因型-蛋白表型-临床表型的相关性。在PubMed和Web of Science中进行检索，对研究设计和发表时间没有任何限制。从174篇符合条件的全文文章中，共调查了1178例患有原发性免疫缺陷病且有553种不同突变的患者。分析了所有突变的突变类型对蛋白质表达和蛋白质功能的影响。此外，对在原发性免疫缺陷病患者中鉴定出的最常见的错义突变和无义突变进行评估，以确定基因型-临床表型的相关性。蛋白质表达和功能因突变类型和受影响结构域而异。在所有调查的患者中，观察到蛋白质表达水平与临床严重程度之间存在显著关系。临床严重程度与受影响结构域之间也存在正相关。在评估临床表型时，应根据蛋白质表达水平和功能变化仔细评估突变类型和受影响结构域。
