Novel DNMT3A Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma

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dc.contributor.authorMellid, Sara
dc.contributor.authorColoma, Javier
dc.contributor.authorCalsina, Bruna
dc.contributor.authorMonteagudo, María
dc.contributor.authorRoldán Romero, Juan M.
dc.contributor.authorSantos, María
dc.contributor.authorLeandro García, Luis J.
dc.contributor.authorLanillos, Javier
dc.contributor.authorMartínez Montes, Ángel M.
dc.contributor.authorRodríguez-Antona, Cristina
dc.contributor.authorMontero Conde, Cristina
dc.contributor.authorMartínez López, Joaquín
dc.contributor.authorAyala, Rosa
dc.contributor.authorMatias-Guiu, Xavier
dc.contributor.authorRobledo, Mercedes
dc.contributor.authorCascón, Alberto
dc.date.accessioned2022-01-26T12:07:54Z
dc.date.available2022-01-26T12:07:54Z
dc.date.issued2020
dc.description.abstractOver the past few years, next generation technologies have been applied to unravel the genetics of rare inherited diseases, facilitating the discovery of new susceptibility genes. We recently found germline DNMT3A gain-of-function variants in two patients with head and neck paragangliomas causing a characteristic hypermethylated DNA profile. Here, whole-exome sequencing identifies a novel germline DNMT3A variant (p.Gly332Arg) in a patient with bilateral carotid paragangliomas, papillary thyroid carcinoma and idiopathic intellectual disability. The variant, located in the Pro-Trp-Trp-Pro (PWWP) domain of the protein involved in chromatin targeting, affects a residue mutated in papillary thyroid tumors and located between the two residues found mutated in microcephalic dwarfism patients. Structural modelling of the variant in the DNMT3A PWWP domain predicts that the interaction with H3K36me3 will be altered. An increased methylation of DNMT3A target genes, compatible with a gain-of-function effect of the alteration, was observed in saliva DNA from the proband and in one independent acute myeloid leukemia sample carrying the same p.Gly332Arg variant. Although further studies are needed to support a causal role of DNMT3A variants in paraganglioma, the description of a new DNMT3A alteration in a patient with multiple clinical features suggests a heterogeneous phenotypic spectrum related to DNMT3A germline variants.ca_ES
dc.description.sponsorshipThis work was supported by the Instituto de Salud Carlos III (ISCIII), through the “Acción Estratégicaen Salud” (AES) (projects PI18/00454 and PI17/01796 to A.C. and M.R., repectively), cofounded by the EuropeanRegional Development Fund (ERDF).ca_ES
dc.identifier.doihttps://doi.org/10.3390/cancers12113304
dc.identifier.issn2072-6694
dc.identifier.urihttp://hdl.handle.net/10459.1/72830
dc.language.isoengca_ES
dc.publisherMDPIca_ES
dc.relation.isformatofReproducció del document publicat a: https://doi.org/10.3390/cancers12113304ca_ES
dc.relation.ispartofCancers 2020, vol. 12, núm. 11ca_ES
dc.rightscc-by (c)authors, 2020ca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessca_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectDNMT3Aca_ES
dc.subjectGermline variantca_ES
dc.subjectPapillary thyroid carcinomaca_ES
dc.subjectParagangliomaca_ES
dc.titleNovel DNMT3A Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinomaca_ES
dc.typeinfo:eu-repo/semantics/articleca_ES
dc.type.versioninfo:eu-repo/semantics/publishedVersionca_ES
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