Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Human mutation, 2016-03, Vol.37 (3), p.301-307

Ort / Verlag

United States: Blackwell Publishing Ltd

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. EZH2 acts within the Polycomb Repressive Complex 2 (PRC2) to repress gene expression. Gain‐of‐function somatic mutations in EZH2, leading to increased trimethylation and thus increased gene repression, have been described in various cancers. Our in vitro data suggests that constitutional mutations of EZH2 observed in Weaver syndrome patients are likely to be loss‐of‐function, thus leading to the loss of gene repression.