Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients

Bruna Calsina; Maria Currás-Freixes; Alexandre Buffet; Tirso Pons; Laura Contreras; Rocío Letón; Iñaki Comino-Méndez; Laura Remacha; María Calatayud; Berta Obispo; Antoine Martin; Regis Cohen; Susan Richter; Judith Balmaña; Esther Korpershoek; Elena Rapizzi; Timo Deutschbein; Laurent Vroonen; Judith Favier; Ronald R. de Krijger; Martin Fassnacht; Felix Beuschlein; Henri J. Timmers; Graeme Eisenhofer; Massimo Mannelli; Karel Pacak; Jorgina Satrústegui; Cristina Rodríguez-Antona; Laurence Amar; Alberto Cascón; Nicole Dölker; Anne Paule Gimenez-Roqueplo; Mercedes Robledo

doi:10.1038/s41436-018-0068-7

Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients

Bruna Calsina, Maria Currás-Freixes, Alexandre Buffet, Tirso Pons, Laura Contreras, Rocío Letón, Iñaki Comino-Méndez, Laura Remacha, María Calatayud, Berta Obispo, Antoine Martin, Regis Cohen, Susan Richter, Judith Balmaña, Esther Korpershoek, Elena Rapizzi, Timo Deutschbein, Laurent Vroonen, Judith Favier, Ronald R. de KrijgerMartin Fassnacht, Felix Beuschlein, Henri J. Timmers, Graeme Eisenhofer, Massimo Mannelli, Karel Pacak, Jorgina Satrústegui, Cristina Rodríguez-Antona, Laurence Amar, Alberto Cascón, Nicole Dölker, Anne Paule Gimenez-Roqueplo, Mercedes Robledo

Research output: Contribution to journal › Article › peer-review

52 Citations (Scopus)

Abstract

Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.

Original language	English
Pages (from-to)	1652-1662
Number of pages	11
Journal	Genetics in Medicine
Volume	20
Issue number	12
DOIs	https://doi.org/10.1038/s41436-018-0068-7
Publication status	Published - 1 Dec 2018
Externally published	Yes

Keywords

Dominant-negative effect
MDH2
Molecular dynamics
pheochromocytoma and paraganglioma
Variants of unknown significance

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10.1038/s41436-018-0068-7

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Calsina, B., Currás-Freixes, M., Buffet, A., Pons, T., Contreras, L., Letón, R., Comino-Méndez, I., Remacha, L., Calatayud, M., Obispo, B., Martin, A., Cohen, R., Richter, S., Balmaña, J., Korpershoek, E., Rapizzi, E., Deutschbein, T., Vroonen, L., Favier, J., ... Robledo, M. (2018). Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients. Genetics in Medicine, 20(12), 1652-1662. https://doi.org/10.1038/s41436-018-0068-7

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title = "Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients",

abstract = "Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.",

keywords = "Dominant-negative effect, MDH2, Molecular dynamics, pheochromocytoma and paraganglioma, Variants of unknown significance",

author = "Bruna Calsina and Maria Curr{\'a}s-Freixes and Alexandre Buffet and Tirso Pons and Laura Contreras and Roc{\'i}o Let{\'o}n and I{\~n}aki Comino-M{\'e}ndez and Laura Remacha and Mar{\'i}a Calatayud and Berta Obispo and Antoine Martin and Regis Cohen and Susan Richter and Judith Balma{\~n}a and Esther Korpershoek and Elena Rapizzi and Timo Deutschbein and Laurent Vroonen and Judith Favier and {de Krijger}, {Ronald R.} and Martin Fassnacht and Felix Beuschlein and Timmers, {Henri J.} and Graeme Eisenhofer and Massimo Mannelli and Karel Pacak and Jorgina Satr{\'u}stegui and Cristina Rodr{\'i}guez-Antona and Laurence Amar and Alberto Casc{\'o}n and Nicole D{\"o}lker and Gimenez-Roqueplo, {Anne Paule} and Mercedes Robledo",

note = "Publisher Copyright: {\textcopyright} 2018, American College of Medical Genetics and Genomics.",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41436-018-0068-7",

language = "English",

volume = "20",

pages = "1652--1662",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier B.V.",

number = "12",

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Calsina, B, Currás-Freixes, M, Buffet, A, Pons, T, Contreras, L, Letón, R, Comino-Méndez, I, Remacha, L, Calatayud, M, Obispo, B, Martin, A, Cohen, R, Richter, S, Balmaña, J, Korpershoek, E, Rapizzi, E, Deutschbein, T, Vroonen, L, Favier, J, de Krijger, RR, Fassnacht, M, Beuschlein, F, Timmers, HJ, Eisenhofer, G, Mannelli, M, Pacak, K, Satrústegui, J, Rodríguez-Antona, C, Amar, L, Cascón, A, Dölker, N, Gimenez-Roqueplo, AP & Robledo, M 2018, 'Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients', Genetics in Medicine, vol. 20, no. 12, pp. 1652-1662. https://doi.org/10.1038/s41436-018-0068-7

TY - JOUR

T1 - Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients

AU - Calsina, Bruna

AU - Currás-Freixes, Maria

AU - Buffet, Alexandre

AU - Pons, Tirso

AU - Contreras, Laura

AU - Letón, Rocío

AU - Comino-Méndez, Iñaki

AU - Remacha, Laura

AU - Calatayud, María

AU - Obispo, Berta

AU - Martin, Antoine

AU - Cohen, Regis

AU - Richter, Susan

AU - Balmaña, Judith

AU - Korpershoek, Esther

AU - Rapizzi, Elena

AU - Deutschbein, Timo

AU - Vroonen, Laurent

AU - Favier, Judith

AU - de Krijger, Ronald R.

AU - Fassnacht, Martin

AU - Beuschlein, Felix

AU - Timmers, Henri J.

AU - Eisenhofer, Graeme

AU - Mannelli, Massimo

AU - Pacak, Karel

AU - Satrústegui, Jorgina

AU - Rodríguez-Antona, Cristina

AU - Amar, Laurence

AU - Cascón, Alberto

AU - Dölker, Nicole

AU - Gimenez-Roqueplo, Anne Paule

AU - Robledo, Mercedes

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.

AB - Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.

KW - Dominant-negative effect

KW - MDH2

KW - Molecular dynamics

KW - pheochromocytoma and paraganglioma

KW - Variants of unknown significance

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U2 - 10.1038/s41436-018-0068-7

DO - 10.1038/s41436-018-0068-7

M3 - Article

C2 - 30008476

AN - SCOPUS:85049899181

SN - 1098-3600

VL - 20

SP - 1652

EP - 1662

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 12

ER -

Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients

Abstract

Keywords

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