Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans

Eevi Kaasinen; Outi Kuismin; Kristiina Rajamäki; Heikki Ristolainen; Mervi Aavikko; Johanna Kondelin; Silva Saarinen; Davide G. Berta; Riku Katainen; Elina A. M. Hirvonen; Auli Karhu; Aurora Taira; Tomas Tanskanen; Amjad Alkodsi; Minna Taipale; Ekaterina Morgunova; Kaarle Franssila; Rainer Lehtonen; Markus J. Mäkinen; Kristiina Aittomäki; Aarno Palotie; Mitja Kurki; Olli Pietiläinen; Morgane Hilpert; Elmo Saarentaus; Jaakko Niinimäki; Juhani Junttila; Kari Kaikkonen; Pia Vahteristo; Radek C. Skoda; Kari K. Eklund; Jussi Taipale; Outi Kilpivaara; Lauri A. Aaltonen

doi:10.1038/s41467-019-09198-7

Key Points

To characterize the clinical and molecular consequences of constitutional TET2 haploinsufficiency in humans, particularly regarding DNA methylation, cytokine expression, and atherosclerosis predisposition.
Identified and analyzed a germline TET2 mutation within a family affected by lymphoma.
Evaluated clinical phenotypes and cytokine/chemokine expression profiles in family members and cells from three additional unrelated germline TET2 mutation carriers.
Analyzed blood DNA methylation patterns across regulatory genomic regions and compared them with data from four individuals carrying germline DNMT3A mutations.
Germline TET2 mutation carriers displayed neither an unusual predisposition to atherosclerosis nor elevated pro-inflammatory cytokine or chemokine expression.
TET2 deficiency caused elevated blood DNA methylation levels concentrated at active enhancers and hematopoietic master transcription factor binding sites.
Regulatory regions with elevated methylation in TET2 carriers showed reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers.

Implication

Reveals altered DNA methylation without increased atherosclerosis in humans with germline TET2 haploinsufficiency, challenging murine cardiovascular disease models.

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Cite This Study

Kaasinen et al. (2019) studied this question.

synapsesocial.com/papers/6aa7fec85ad6eac31cb17e72 https://doi.org/10.1038/s41467-019-09198-7

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Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans

Key Points

Implication

Abstract

Discussion

Cite This Study

Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans

Key Points

Implication

Abstract

Discussion

Cite This Study

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