oru.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Ezh2 mutations found in the Weaver overgrowth syndrome cause a partial loss of H3K27 histone methyltransferase activity
National Institutes of Health, .
Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA.
Genetic Engineering Core, National Eye Institute, National Institutes of Health, Bethesda MD, USA.
Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA.
Show others and affiliations
2018 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 4, p. 1470-1478Article in journal (Refereed) Published
Abstract [en]

Context: Weaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations in EZH2, a histone methyltransferase responsible for H3K27 trimethylation. However, no early truncating mutations have been identified, suggesting that null mutations do not cause Weaver syndrome.

Objective: To test alternative hypotheses that EZH2 variants found in Weaver syndrome either cause a gain of function or a partial loss of function.

Design: Exome sequencing was performed in a boy with tall stature, advanced bone age, and mild dysmorphic features. Mutant or wild-type EZH2 protein was expressed in mouse growth plate chondrocytes with or without endogenous EZH2, and enzymatic activity was measured. A mouse model was generated, and histone methylation was assessed in heterozygous and homozygous embryos.

Results: A de novo missense EZH2 mutation (c.1876G>A (p.Val626Met)) was identified in the proband. When expressed in growth plate chondrocytes, the mutant protein showed decreased histone methyltransferase activity. A mouse model carrying this EZH2 mutation was generated using CRISPR/Cas9. Homozygotes showed perinatal lethality while heterozygotes were viable, fertile, and showed mild overgrowth. Both homozygous and heterozygous embryos showed decreased H3K27 methylation.

Conclusion: We generated a mouse model with the same mutation as our patient and found that it recapitulates the Weaver overgrowth phenotype, and demonstrated that EZH2 mutations found in Weaver syndrome cause a partial loss of function.

Place, publisher, year, edition, pages
Cary, NC, United States: Oxford University Press, 2018. Vol. 103, no 4, p. 1470-1478
National Category
Medical Genetics Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:oru:diva-63399DOI: 10.1210/jc.2017-01948ISI: 000429442000027PubMedID: 29244146Scopus ID: 2-s2.0-85045423542OAI: oai:DiVA.org:oru-63399DiVA, id: diva2:1171924
Note

Funding Agency:

Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH)

Available from: 2018-01-08 Created: 2018-01-08 Last updated: 2018-08-13Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMedScopus

Authority records BETA

Nilsson, Ola

Search in DiVA

By author/editor
Nilsson, Ola
By organisation
School of Medical Sciences
In the same journal
Journal of Clinical Endocrinology and Metabolism
Medical GeneticsEndocrinology and Diabetes

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 5 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf