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Hum Mutat. 2016 Mar;37(3):301-7. doi: 10.1002/humu.22946. Epub 2016 Jan 12.

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

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Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
Child and Family Research Institute, Vancouver, British Columbia, V5Z 4H4, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 2B5, Canada.
Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, V5Z 1L3, Canada.
Children's and Women's Health Centre of British Columbia, Vancouver, British Columbia, V6H 3N1, Canada.
Department of Medical Genetics, Complejo Hospitalario de Navarra, IdiSNA, Navarra Institute for Health Research, Pamplona, 31008, Spain.
Medical Genetics Service, Medical Genetics Center Dr. Jacinto Magalhães, Porto Hospital Center, EPE, Porto, 4099-001, Portugal.
Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico Universitario Agostino Gemelli, Roma, 00168, Italy.
Service de Génétique Clinique, Centre de Référence Anomalies du Développement, CHU Rennes, Rennes, 35203, France.
Department of Pediatrics, Division of Translation Therapeutics, University of British Columbia, Vancouver, British Columbia, V6H 3V4, Canada.
Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, Washington, 98101.
Department of Pediatrics, University of Washington, Seattle, Washington, 98195.
Department of Neurology, University of Washington, Seattle, Washington, 98105.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, 46202-5251.


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; H3K27; Weaver syndrome; childhood cancer; histone methyltransferase

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