Weaver Syndrome-Associated EZH2 Protein Variants Show Impaired Histone Methyltransferase Function In Vitro

Ana S.A. Cohen, Damian B. Yap, M. E.Suzanne Lewis, Chieko Chijiwa, Maria A. Ramos-Arroyo, Natália Tkachenko, Valentina Milano, Mélanie Fradin, Margaret L. Mckinnon, Katelin N. Townsend, Jieqing Xu, M. I. Van Allen, Colin J.D. Ross, William B. Dobyns, David D. Weaver, William T. Gibson

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual disability, and susceptibility to cancers. De novo mutations in the enhancer of zeste homolog 2 (EZH2) have been shown to cause WS. EZH2 is a histone methyltransferase that acts as the catalytic agent of the polycomb-repressive complex 2 (PRC2) to maintain gene repression via methylation of lysine 27 on histone H3 (H3K27). Functional studies investigating histone methyltransferase activity of mutant EZH2 from various cancers have been reported, whereas WS-associated mutations remain poorly characterized. To investigate the role of EZH2 in WS, we performed functional studies using artificially assembled PRC2 complexes containing mutagenized human EZH2 that reflected the codon changes predicted from patients with WS. We found that WS-associated amino acid alterations reduce the histone methyltransferase function of EZH2 in this in vitro assay. Our results support the hypothesis that WS is caused by constitutional mutations in EZH2 that alter the histone methyltransferase function of PRC2. However, histone methyltransferase activities of different EZH2 variants do not appear to correlate directly with the phenotypic variability between WS patients and individuals with a common c.553G>C (p.Asp185His) polymorphism in EZH2.

Original languageEnglish (US)
Pages (from-to)301-307
Number of pages7
JournalHuman Mutation
Volume37
Issue number3
DOIs
StatePublished - Mar 1 2016

Keywords

  • Childhood cancer
  • EZH2
  • H3K27
  • Histone methyltransferase
  • Weaver syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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  • Cite this

    Cohen, A. S. A., Yap, D. B., Lewis, M. E. S., Chijiwa, C., Ramos-Arroyo, M. A., Tkachenko, N., Milano, V., Fradin, M., Mckinnon, M. L., Townsend, K. N., Xu, J., Van Allen, M. I., Ross, C. J. D., Dobyns, W. B., Weaver, D. D., & Gibson, W. T. (2016). Weaver Syndrome-Associated EZH2 Protein Variants Show Impaired Histone Methyltransferase Function In Vitro. Human Mutation, 37(3), 301-307. https://doi.org/10.1002/humu.22946