Functional and in silico assessment of MAX variants of unknown significance

2.50
Hdl Handle:
http://hdl.handle.net/11287/594020
Title:
Functional and in silico assessment of MAX variants of unknown significance
Authors:
Comino-Mendez, I.; Leandro-Garcia, L. J.; Montoya, G.; Inglada-Perez, L.; de Cubas, A. A.; Curras-Freixes, M.; Tysoe, Carolyn; Izatt, L.; Leton, R.; Gomez-Grana, A.; Mancikova, V.; Apellaniz-Ruiz, M.; Mannelli, M.; Schiavi, F.; Favier, J.; Gimenez-Roqueplo, A. P.; Timmers, H. J.; Roncador, G.; Garcia, J. F.; Rodriguez-Antona, C.; Robledo, M.; Cascon, A.
Abstract:
The presence of germline mutations affecting the MYC-associated protein X (MAX) gene has recently been identified as one of the now 11 major genetic predisposition factors for the development of hereditary pheochromocytoma and/or paraganglioma. Little is known regarding how missense variants of unknown significance (VUS) in MAX affect its pivotal role in the regulation of the MYC/MAX/MXD axis. In the present study, we propose a consensus computational prediction based on five "state-of-the-art" algorithms. We also describe a PC12-based functional assay to assess the effects that 12 MAX VUS may have on MYC's E-box transcriptional activation. For all but two of these 12 VUS, the functional assay and the consensus computational prediction gave consistent results; we classified seven variants as pathogenic and three as nonpathogenic. The introduction of wild-type MAX cDNA into PC12 cells significantly decreased MYC's ability to bind to canonical E-boxes, while pathogenic MAX proteins were not able to fully repress MYC activity. Further clinical and molecular evaluation of variant carriers corroborated the results obtained with our functional assessment. In the absence of clear heritability, clinical information, and molecular data, consensus computational predictions and functional models are able to correctly classify VUS affecting MAX. KEY MESSAGES: A functional assay assesses the effects of MAX VUS over MYC transcriptional activity. A consensus computational prediction and the functional assay show high concordance. Variant carriers' clinical and molecular data support the functional assessment.
Citation:
J Mol Med (Berl). 2015 Nov;93(11):1247-55.
Publisher:
Springer
Journal:
Journal of molecular medicine
Issue Date:
Nov-2015
URI:
http://hdl.handle.net/11287/594020
DOI:
10.1007/s00109-015-1306-y
PubMed ID:
26070438
Additional Links:
http://dx.doi.org/10.1007/s00109-015-1306-y
Type:
Journal Article
Language:
eng
ISSN:
1432-1440
Appears in Collections:
2015 RD&E publications; Molecular Genetics

Full metadata record

DC FieldValue Language
dc.contributor.authorComino-Mendez, I.en
dc.contributor.authorLeandro-Garcia, L. J.en
dc.contributor.authorMontoya, G.en
dc.contributor.authorInglada-Perez, L.en
dc.contributor.authorde Cubas, A. A.en
dc.contributor.authorCurras-Freixes, M.en
dc.contributor.authorTysoe, Carolynen
dc.contributor.authorIzatt, L.en
dc.contributor.authorLeton, R.en
dc.contributor.authorGomez-Grana, A.en
dc.contributor.authorMancikova, V.en
dc.contributor.authorApellaniz-Ruiz, M.en
dc.contributor.authorMannelli, M.en
dc.contributor.authorSchiavi, F.en
dc.contributor.authorFavier, J.en
dc.contributor.authorGimenez-Roqueplo, A. P.en
dc.contributor.authorTimmers, H. J.en
dc.contributor.authorRoncador, G.en
dc.contributor.authorGarcia, J. F.en
dc.contributor.authorRodriguez-Antona, C.en
dc.contributor.authorRobledo, M.en
dc.contributor.authorCascon, A.en
dc.date.accessioned2016-01-19T12:38:41Zen
dc.date.available2016-01-19T12:38:41Zen
dc.date.issued2015-11en
dc.identifier.citationJ Mol Med (Berl). 2015 Nov;93(11):1247-55.en
dc.identifier.issn1432-1440en
dc.identifier.pmid26070438en
dc.identifier.doi10.1007/s00109-015-1306-yen
dc.identifier.urihttp://hdl.handle.net/11287/594020en
dc.description.abstractThe presence of germline mutations affecting the MYC-associated protein X (MAX) gene has recently been identified as one of the now 11 major genetic predisposition factors for the development of hereditary pheochromocytoma and/or paraganglioma. Little is known regarding how missense variants of unknown significance (VUS) in MAX affect its pivotal role in the regulation of the MYC/MAX/MXD axis. In the present study, we propose a consensus computational prediction based on five "state-of-the-art" algorithms. We also describe a PC12-based functional assay to assess the effects that 12 MAX VUS may have on MYC's E-box transcriptional activation. For all but two of these 12 VUS, the functional assay and the consensus computational prediction gave consistent results; we classified seven variants as pathogenic and three as nonpathogenic. The introduction of wild-type MAX cDNA into PC12 cells significantly decreased MYC's ability to bind to canonical E-boxes, while pathogenic MAX proteins were not able to fully repress MYC activity. Further clinical and molecular evaluation of variant carriers corroborated the results obtained with our functional assessment. In the absence of clear heritability, clinical information, and molecular data, consensus computational predictions and functional models are able to correctly classify VUS affecting MAX. KEY MESSAGES: A functional assay assesses the effects of MAX VUS over MYC transcriptional activity. A consensus computational prediction and the functional assay show high concordance. Variant carriers' clinical and molecular data support the functional assessment.en
dc.language.isoengen
dc.publisherSpringeren
dc.relation.urlhttp://dx.doi.org/10.1007/s00109-015-1306-yen
dc.titleFunctional and in silico assessment of MAX variants of unknown significanceen
dc.typeJournal Articleen
dc.identifier.journalJournal of molecular medicineen

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