随着心肌病的遗传前景不断扩大,疾病相关基因中错义变异的鉴定经常导致不确定显著性变异(VUS)的分类.为了对这些变体进行适当的重新分类,功能表征是正确评估致病潜力的重要因素。钙转运调节蛋白磷脂中的几种错义变体与扩张型心肌病有关。然而,目前已知该跨膜肽中的>40个错义变体,并且大多数仍然分类为VUS,几乎没有临床信息。同样,心肌肌球蛋白结合蛋白的错义变异与肥厚型心肌病有关。然而,已知有数百种变体,其中许多具有低外显率,并且经常在对照人群中发现。在这里,我们专注于pholinamban中的新错义变体,在4岁女性中发现的Ala15-Thr变体和在60岁女性中发现的Pro21-Thr变体,均有扩张型心肌病的家族史和临床诊断。患者还在心脏肌球蛋白结合蛋白中携带Val896-Met变体。磷脂变体导致功能缺陷,磷酸化,和钙转运调节肽的去磷酸化,我们将这些变种归类为潜在致病的。心脏肌球蛋白结合蛋白中的变体改变了蛋白质的结构。虽然这种变体被归类为良性的,由于心肌肌球蛋白结合蛋白的结构改变,它有可能成为低风险易感变异体.我们的研究为以前分类为良性或VUS的错义变异提供了新的生化证据。
As the genetic landscape of cardiomyopathies continues to expand, the identification of missense variants in disease-associated genes frequently leads to a classification of variant of uncertain significance (VUS). For the proper reclassification of such variants, functional characterization is an important contributor to the proper assessment of pathogenic potential. Several missense variants in the calcium transport regulatory protein
phospholamban have been associated with dilated cardiomyopathy. However, >40 missense variants in this transmembrane peptide are currently known and most remain classified as VUS with little clinical information. Similarly, missense variants in cardiac myosin binding protein have been associated with hypertrophic cardiomyopathy. However, hundreds of variants are known and many have low penetrance and are often found in control populations. Herein, we focused on novel missense variants in
phospholamban, an Ala15-Thr variant found in a 4-year-old female and a Pro21-Thr variant found in a 60-year-old female, both with a family history and clinical diagnosis of dilated cardiomyopathy. The patients also harbored a Val896-Met variant in cardiac myosin binding protein. The
phospholamban variants caused defects in the function, phosphorylation, and dephosphorylation of this calcium transport regulatory peptide, and we classified these variants as potentially pathogenic. The variant in cardiac myosin binding protein alters the structure of the protein. While this variant has been classified as benign, it has the potential to be a low-risk susceptibility variant because of the structural change in cardiac myosin binding protein. Our studies provide new biochemical evidence for missense variants previously classified as benign or VUS.