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Novel Germline SUCLG2 Mutations in Patients With Pheochromocytoma and Paraganglioma

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells that are frequently linked to mutations including those in Krebs cycle enzymes, particularly succinate dehydrogenase (SDH). Succinyl-CoA ligase (SUCL) catalyzes reversible conversion of succin...

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Autores principales: Vanova, Katerina Hadrava, Pang, Ying, Krobova, Linda, Kraus, Michal, Nahacka, Zuzana, Boukalova, Stepana, Pack, Svetlana, Zobalova, Renata, Zhu, Jun, Huynh, Thanh, Jochmanova, Ivana, Uher, Ondrej, Hubackova, Sona, Dvorakova, Sarka, Garrett, Timothy, Ghayee, Hans, Schuster, Bjoern, Knapp, Philip, Frysak, Zdenek, Hartmann, Igor, Nilubol, Naris, Cerny, Jiri, Taieb, David, Rohlena, Jakub, Neuzil, Jiri, Yang, Chun Zhang, Pacak, Karel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265745/
http://dx.doi.org/10.1210/jendso/bvab048.340
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author Vanova, Katerina Hadrava
Pang, Ying
Krobova, Linda
Kraus, Michal
Nahacka, Zuzana
Boukalova, Stepana
Pack, Svetlana
Zobalova, Renata
Zhu, Jun
Huynh, Thanh
Jochmanova, Ivana
Uher, Ondrej
Hubackova, Sona
Dvorakova, Sarka
Garrett, Timothy
Ghayee, Hans
Schuster, Bjoern
Knapp, Philip
Frysak, Zdenek
Hartmann, Igor
Nilubol, Naris
Cerny, Jiri
Taieb, David
Rohlena, Jakub
Neuzil, Jiri
Yang, Chun Zhang
Pacak, Karel
author_facet Vanova, Katerina Hadrava
Pang, Ying
Krobova, Linda
Kraus, Michal
Nahacka, Zuzana
Boukalova, Stepana
Pack, Svetlana
Zobalova, Renata
Zhu, Jun
Huynh, Thanh
Jochmanova, Ivana
Uher, Ondrej
Hubackova, Sona
Dvorakova, Sarka
Garrett, Timothy
Ghayee, Hans
Schuster, Bjoern
Knapp, Philip
Frysak, Zdenek
Hartmann, Igor
Nilubol, Naris
Cerny, Jiri
Taieb, David
Rohlena, Jakub
Neuzil, Jiri
Yang, Chun Zhang
Pacak, Karel
author_sort Vanova, Katerina Hadrava
collection PubMed
description Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells that are frequently linked to mutations including those in Krebs cycle enzymes, particularly succinate dehydrogenase (SDH). Succinyl-CoA ligase (SUCL) catalyzes reversible conversion of succinyl-CoA to succinate providing the substrate for SDH. While mitochondrial diseases were documented for the mutations in SUCL subunits G1 and A2, the association of GDP/GTP-specific subunit SUCLG2 mutations with specific pathologies including cancer have not been reported. In our study, 352 patients with apparently sporadic PPGLs underwent genetic testing using a panel of 54 genes developed at the National Institutes of Health. Additionally, human pheochromocytoma (hPheo1) cells were used for gene manipulation to produce SUCLG2 knock-out (KO). Tumor tissues and hPheo1 SUCLG2 KO cells were used for further analysis focusing on mechanism of germline variants effect on mitochondrial functions. We detected eight germline SUCLG2 mutations in 15 patients which represents 4.3% of the cohort. Germline variants together with LOH led to decreased levels of SDH subunit B resulting in aberrant respiration and accumulation of succinate, well recognized oncometabolite. Manipulation of SUCLG2 in hPheo1 cells confirmed decrease in SDHB leading to faulty assembly of mitochondrial complex II and alteration of its respiration and activity. In summary, our study identified an association between SUCLG2 and PPGL. Larger scale sequencing and uncovering additional cases bearing SUCLG2 variants will further clarify the relationship between SUCLG2 and SDHx, particularly SDHB, as well as their role in disease etiology.
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spelling pubmed-82657452021-07-09 Novel Germline SUCLG2 Mutations in Patients With Pheochromocytoma and Paraganglioma Vanova, Katerina Hadrava Pang, Ying Krobova, Linda Kraus, Michal Nahacka, Zuzana Boukalova, Stepana Pack, Svetlana Zobalova, Renata Zhu, Jun Huynh, Thanh Jochmanova, Ivana Uher, Ondrej Hubackova, Sona Dvorakova, Sarka Garrett, Timothy Ghayee, Hans Schuster, Bjoern Knapp, Philip Frysak, Zdenek Hartmann, Igor Nilubol, Naris Cerny, Jiri Taieb, David Rohlena, Jakub Neuzil, Jiri Yang, Chun Zhang Pacak, Karel J Endocr Soc Adrenal Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells that are frequently linked to mutations including those in Krebs cycle enzymes, particularly succinate dehydrogenase (SDH). Succinyl-CoA ligase (SUCL) catalyzes reversible conversion of succinyl-CoA to succinate providing the substrate for SDH. While mitochondrial diseases were documented for the mutations in SUCL subunits G1 and A2, the association of GDP/GTP-specific subunit SUCLG2 mutations with specific pathologies including cancer have not been reported. In our study, 352 patients with apparently sporadic PPGLs underwent genetic testing using a panel of 54 genes developed at the National Institutes of Health. Additionally, human pheochromocytoma (hPheo1) cells were used for gene manipulation to produce SUCLG2 knock-out (KO). Tumor tissues and hPheo1 SUCLG2 KO cells were used for further analysis focusing on mechanism of germline variants effect on mitochondrial functions. We detected eight germline SUCLG2 mutations in 15 patients which represents 4.3% of the cohort. Germline variants together with LOH led to decreased levels of SDH subunit B resulting in aberrant respiration and accumulation of succinate, well recognized oncometabolite. Manipulation of SUCLG2 in hPheo1 cells confirmed decrease in SDHB leading to faulty assembly of mitochondrial complex II and alteration of its respiration and activity. In summary, our study identified an association between SUCLG2 and PPGL. Larger scale sequencing and uncovering additional cases bearing SUCLG2 variants will further clarify the relationship between SUCLG2 and SDHx, particularly SDHB, as well as their role in disease etiology. Oxford University Press 2021-05-03 /pmc/articles/PMC8265745/ http://dx.doi.org/10.1210/jendso/bvab048.340 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Adrenal
Vanova, Katerina Hadrava
Pang, Ying
Krobova, Linda
Kraus, Michal
Nahacka, Zuzana
Boukalova, Stepana
Pack, Svetlana
Zobalova, Renata
Zhu, Jun
Huynh, Thanh
Jochmanova, Ivana
Uher, Ondrej
Hubackova, Sona
Dvorakova, Sarka
Garrett, Timothy
Ghayee, Hans
Schuster, Bjoern
Knapp, Philip
Frysak, Zdenek
Hartmann, Igor
Nilubol, Naris
Cerny, Jiri
Taieb, David
Rohlena, Jakub
Neuzil, Jiri
Yang, Chun Zhang
Pacak, Karel
Novel Germline SUCLG2 Mutations in Patients With Pheochromocytoma and Paraganglioma
title Novel Germline SUCLG2 Mutations in Patients With Pheochromocytoma and Paraganglioma
title_full Novel Germline SUCLG2 Mutations in Patients With Pheochromocytoma and Paraganglioma
title_fullStr Novel Germline SUCLG2 Mutations in Patients With Pheochromocytoma and Paraganglioma
title_full_unstemmed Novel Germline SUCLG2 Mutations in Patients With Pheochromocytoma and Paraganglioma
title_short Novel Germline SUCLG2 Mutations in Patients With Pheochromocytoma and Paraganglioma
title_sort novel germline suclg2 mutations in patients with pheochromocytoma and paraganglioma
topic Adrenal
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265745/
http://dx.doi.org/10.1210/jendso/bvab048.340
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