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Mouse imprinting defect mutations that model Angelman syndrome.
Mei-Yi Wu1, Ken-Shiung Chen, Jan Bressler
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Genesis (New York, N.Y. : 2000)
|January 7, 2006
Summary
Researchers identified mouse mutations mimicking Angelman syndrome (AS) imprinting defects. These mutations on the maternal chromosome conferred a paternal epigenotype, rescuing Prader-Willi syndrome (PWS) models.
Area of Science:
- Genetics
- Developmental Biology
- Neurogenetics
Background:
- Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurobehavioral disorders caused by imprinting defects on human chromosome 15q11-15q13.
- Gene expression in this region is regulated by a bipartite imprinting center (IC).
- Human PWS-IC and AS-IC have been localized to specific DNA regions.
Purpose of the Study:
- To investigate mouse models with defects similar to human Angelman syndrome caused by AS-IC deletion.
- To determine if these mouse mutations affect imprinting and gene expression.
- To assess the functional consequence of these imprinting defects in PWS models.
Main Methods:
- Generation and characterization of two mouse mutations affecting the region upstream of Snrpn.
- Analysis of DNA methylation at the maternal Snrpn promoter.
- Assessment of gene expression patterns for paternally and maternally repressed genes.
- Testing the ability of mutant maternal chromosomes to rescue a PWS mouse model.
Main Results:
- An insertion/duplication mutation resulted in loss of maternal methylation at the Snrpn promoter, activating maternal genes and repressing paternal genes.
- This mutation conferred a paternal epigenotype to the maternal chromosome, rescuing PWS model lethality and growth retardation.
- An 80-kb deletion mutation caused similar imprinting defects with variable penetrance.
Conclusions:
- The identified mouse mutations functionally mimic human AS-IC deletion defects.
- These findings demonstrate a conserved imprinting regulatory mechanism between humans and mice.
- A functional equivalent of the human AS-IC exists in mice.
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