Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients

Genetics in Medicine : Official Journal of the American College of Medical Genetics
Bruna CalsinaMercedes Robledo

Abstract

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...Continue Reading

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Citations

Feb 7, 2019·Histochemistry and Cell Biology·Thomas G PapathomasAxel Karl Walch
May 19, 2019·Cancers·Alberto CascónMercedes Robledo
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Methods Mentioned

BETA
enzymatic
transfection
confocal microscopy

Software Mentioned

MetaLR
Pymol
PoPMu
ESE
PROVEAN
RESCUE
Structure
phastCons
phyloP
MutationAssessor

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