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Ezh2 mutations foun...
Ezh2 mutations found in the Weaver overgrowth syndrome cause a partial loss of H3K27 histone methyltransferase activity
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- Lui, Julian C. (författare)
- National Institutes of Health,
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- Barnes, Kevin M. (författare)
- Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA
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- Dong, Lijin (författare)
- Genetic Engineering Core, National Eye Institute, National Institutes of Health, Bethesda MD, USA
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- Yue, Shanna (författare)
- Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA
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- Graber, Evan (författare)
- Division of Pediatric Endocrinology and Diabetes, Ichan School of Medicine at Mount Sinai, New York NY, USA
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- Rapaport, Robert (författare)
- Division of Pediatric Endocrinology and Diabetes, Ichan School of Medicine at Mount Sinai, New York NY, USA
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- Dauber, Andrew (författare)
- Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA
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- Nilsson, Ola, 1970- (författare)
- Karolinska Institutet,Örebro universitet,Institutionen för medicinska vetenskaper,Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA; Center for Molecular Medicine and Pediatric Endocrinology Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden; Örebro University Hosptial, Örebro, Sweden
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- Baron, Jeffrey (författare)
- Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA
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(creator_code:org_t)
- 2017-12-13
- 2018
- Engelska.
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - Cary, NC, United States : Oxford University Press. - 0021-972X .- 1945-7197. ; 103:4, s. 1470-1478
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https://academic.oup...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
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- Av författaren/redakt...
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Lui, Julian C.
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Barnes, Kevin M.
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Dong, Lijin
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Yue, Shanna
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Graber, Evan
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Rapaport, Robert
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visa fler...
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Dauber, Andrew
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Nilsson, Ola, 19 ...
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Baron, Jeffrey
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Örebro universitet
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Karolinska Institutet