Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
INSERM, UMR970, Paris Cardiovascular Research Center and Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine; Equipe labellisée Ligue contre le cancer, Paris, France.
Genet Med. 2018 Dec;20(12):1652-1662. doi: 10.1038/s41436-018-0068-7. Epub 2018 Jul 16.
MDH2 (malate dehydrogenase 2) has recently been proposed as a novel potential pheochromocytoma/paraganglioma (PPGL) susceptibility gene, but its role in the disease has not been addressed. This study aimed to determine the prevalence of MDH2 pathogenic variants among PPGL patients and determine the associated phenotype.
Eight hundred thirty patients with PPGLs, negative for the main PPGL driver genes, were included in the study. Interpretation of variants of unknown significance (VUS) was performed using an algorithm based on 20 computational predictions, by implementing cell-based enzymatic and immunofluorescence assays, and/or by using a molecular dynamics simulation approach.
Five variants with potential involvement in pathogenicity were identified: three missense (p.Arg104Gly, p.Val160Met and p.Ala256Thr), one in-frame deletion (p.Lys314del), and a splice-site variant (c.429+1G>T). All were germline and those with available biochemical data, corresponded to noradrenergic PPGL.
This study suggests that MDH2 pathogenic variants may play a role in PPGL susceptibility and that they might be responsible for less than 1% of PPGLs in patients without pathogenic variants in other major PPGL driver genes, a prevalence similar to the one recently described for other PPGL genes. However, more epidemiological data are needed to recommend MDH2 testing in patients negative for other major PPGL genes.
苹果酸脱氢酶 2（MDH2）最近被提议为一种新的潜在嗜铬细胞瘤/副神经节瘤（PPGL）易感性基因，但它在该疾病中的作用尚未得到解决。本研究旨在确定 MDH2 致病性变异在 PPGL 患者中的流行率，并确定相关表型。
本研究纳入了 830 名 PPGL 患者，这些患者的主要 PPGL 驱动基因均为阴性。使用基于 20 种计算预测的算法对未知意义变异（VUS）进行解释，通过实施基于细胞的酶和免疫荧光测定，和/或使用分子动力学模拟方法来进行。
确定了五个具有潜在致病性的变体：三个错义（p.Arg104Gly、p.Val160Met 和 p.Ala256Thr），一个框内缺失（p.Lys314del），和一个剪接位点变体（c.429+1G>T）。所有这些都是胚系的，并且那些具有可用生化数据的变体与去甲肾上腺素能 PPGL 相对应。
本研究表明，MDH2 致病性变异可能在 PPGL 易感性中起作用，并且它们可能在没有其他主要 PPGL 驱动基因致病性变异的 PPGL 患者中占不到 1%，这一患病率与最近描述的其他 PPGL 基因相似。然而，需要更多的流行病学数据来建议在其他主要 PPGL 基因阴性的患者中进行 MDH2 检测。
