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Two mouse models carrying truncating mutations in Magel2 show distinct phenotypes
Daisuke Ieda1, Yutaka Negishi1, Tomomi Miyamoto2
1Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Plos One
|August 18, 2020
Summary
Researchers investigated Schaaf-Yang syndrome (SYS), a neurodevelopmental disorder caused by MAGEL2 variants. Mouse models suggest that simple toxic gain-of-function effects may not fully explain SYS, indicating complex pathogenic mechanisms for MAGEL2 variants.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Schaaf-Yang syndrome (SYS) is a neurodevelopmental disorder linked to truncating variants in the paternal MAGEL2 allele.
- SYS shares some phenotypes with Prader-Willi syndrome (PWS) but also presents unique features like autism spectrum disorder and joint contractures.
Purpose of the Study:
- To investigate the pathogenic mechanisms of Schaaf-Yang syndrome (SYS).
- To test the hypothesis that truncated MAGEL2 protein causes gain-of-function toxic effects.
Main Methods:
- Generated two mouse models: an overexpression model and a CRISPR/Cas9-edited genome model with a MAGEL2 frameshift variant.
- Analyzed embryonic/neonatal lethality in the overexpression model.
- Assessed phenotypes, including weight and imprinting, in the genome-edited model (Magel2P:fs and Magel2M:fs).
Main Results:
- The MAGEL2 overexpression model exhibited embryonic or neonatal lethality, suggesting toxic effects.
- The genome-edited model maintained MAGEL2 imprinting and transcript distribution but only partially recapitulated SYS phenotypes.
- Neonatal Magel2P:fs mice showed reduced weight, which normalized by adulthood.
Conclusions:
- Simple gain-of-function toxic effects may not solely explain the pathophysiology of Schaaf-Yang syndrome.
- The results suggest a broader range of pathomechanisms for MAGEL2 variants in SYS, similar to observed human patient variability.
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