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Genet Med. 2018 Jul 16. doi: 10.1038/s41436-018-0068-7. [Epub ahead of print]

Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients.

Author information

1
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
2
INSERM, UMR970, Paris Cardiovascular Research Center and Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine; Equipe labellisée Ligue contre le cancer, Paris, France.
3
Structural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
4
Department of Immunology and Oncology, National Centre for Biotechnology (CNB-CSIC), Madrid, Spain.
5
Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa UAM-CSIC, Universidad Autónoma de Madrid and Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain.
6
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
7
Department of Endocrinology and Nutrition Service, Hospital Universitario 12 de Octubre, Madrid, Spain.
8
Servicio Oncología Médica, Hospital Infanta Leonor, Vallecas, Madrid, Spain.
9
Assistance Publique Hôpitaux de Paris; Hôpital Avicenne, Service d'anatomie et cytologie pathologiques, Bobigny, France.
10
INSERM, U978, Université Paris 13, Sorbonne Paris Cité, Bobigny, France.
11
Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Service de Médecine Interne, Bobigny, France.
12
Université Paris 13, Sorbonne Paris Cité, Bobigny, France.
13
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
14
High Risk and Cancer Prevention Group, Medical Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain.
15
Department of Pathology, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
16
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
17
Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany.
18
Department of Endocrinology, Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium.
19
Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
20
Department of Pathology, Reinier de Graaf Hospital, Delft, The Netherlands.
21
Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
22
Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zürich, Switzerland.
23
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
24
Department of Medicine III, University Hospital and Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
25
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
26
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France.
27
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou (HEGP), Department of Genetics, Paris, France.
28
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. mrobledo@cnio.es.
29
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. mrobledo@cnio.es.

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; Variants of unknown significance; pheochromocytoma and paraganglioma

PMID:
30008476
DOI:
10.1038/s41436-018-0068-7

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