TET2 missense variants in human neoplasia. A proposal of structural and functional classification
Bussaglia, Elena (Institut d'Investigació Biomèdica Sant Pau)
Antón, Rosa (Institut d'Investigació Biomèdica Sant Pau)
Nomdedeu, Josep (Institut d'Investigació Biomèdica Sant Pau)
Fuentes-Prior, Pablo (Institut d'Investigació Biomèdica Sant Pau)
Universitat Autònoma de Barcelona

Date:	2019
Abstract:	The human TET2 gene plays a pivotal role in the epigenetic regulation of normal and malignant hematopoiesis. Somatic TET2 mutations have been repeatedly identified in age-related clonal hematopoiesis and in myeloid neoplasms ranging from acute myeloid leukemia (AML) to myeloproliferative neoplasms. However, there have been no attempts to systematically explore the structural and functional consequences of the hundreds of TET2 missense variants reported to date. We have sequenced the TET2 gene in 189 Spanish AML patients using Sanger sequencing and NGS protocols. Next, we performed a thorough bioinformatics analysis of TET2 protein and of the expected impact of all reported TET2 missense variants on protein structure and function, exploiting available structure-and-function information as well as 3D structure prediction tools. We have identified 38 TET2 allelic variants in the studied patients, including two frequent SNPs: p. G355D (10 cases) and p. I1762V (28 cases). Four of the detected mutations are reported here for the first time: c. 122C>T (p. P41L), c. 4535C>G (p. A1512G), c. 4760A>G (p. D1587G), and c. 5087A>T (p. Y1696F). We predict a complex multidomain architecture for the noncatalytic regions of TET2, and in particular the presence of well-conserved α+β globular domains immediately preceding and following the actual catalytic unit. Further, we provide a rigorous interpretation of over 430 missense SNVs that affect the TET2 catalytic domain, and we hypothesize explanations for ~700 additional variants found within the regulatory regions of the protein. Finally, we propose a systematic classification of all missense mutants and SNPs reported to date into three major categories (severe, moderate, and mild), based on their predicted structural and functional impact. The proposed classification of missense TET2 variants would help to assess their clinical impact on human neoplasia and may guide future structure-and-function investigations of TET family members.
Grants:	Ministerio de Economía y Competitividad SAF2014-57994-R
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	5-methylcytosine ; Classification of mutations ; Epigenetic regulation ; Neoplasia ; TET2
Published in:	Molecular genetics & genomic medicine, Vol. 7 Núm. 7 (july 2019) , p. e00772, ISSN 2324-9269

DOI: 10.1002/mgg3.772
PMID: 31187595

13 p, 1.6 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles