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2023 ACMG Annual Clinical Genetics Meeting Digital ...
Initial Characterization of a Novel Mouse Model of ...
Initial Characterization of a Novel Mouse Model of Autosomal Dominant LZTR1-Noonan Syndrome
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A recent study investigated a novel mouse model of autosomal dominant LZTR1-Noonan syndrome, a genetic disorder characterized by facial features, cardiac defects, short stature, and developmental delay. The study aimed to compare the phenotype of mice with a missense allele of the LZTR1 gene (modeling autosomal dominant LZTR1-Noonan syndrome) to mice with a null allele (modeling autosomal recessive LZTR1-Noonan syndrome). <br /><br />Previous research has shown that LZTR1 is the only gene known to cause both autosomal dominant and autosomal recessive LZTR1-Noonan syndrome. Autosomal dominant LZTR1-Noonan syndrome is commonly associated with missense variants in the Kelch domains of the LZTR1 protein, while autosomal recessive LZTR1-Noonan syndrome is typically caused by null variants in the BTB-BACK domain.<br /><br />The study utilized CRISPR/Cas9 genome editing to generate mice with a specific variant in the LZTR1 gene corresponding to a human variant associated with Noonan syndrome. The researchers observed that mice with the missense variant had distinct phenotypes compared to mice with the null variant. However, the breeding of mice with the missense variant resulted in poor outcomes and small litter sizes.<br /><br />Preliminary analyses showed differences in the heart and skull measurements between the wild-type and missense variant mice, indicating potential cardiovascular abnormalities. The researchers also investigated the protein expression levels of RIT1, a protein involved in the Ras/MAPK pathway, and found alterations in the missense and null variant mice compared to the wild type.<br /><br />The study highlighted the need for further analysis with larger sample sizes to understand the specific effects of the missense variant on cardiac and cranial phenotypes. Additionally, future research aims to model potentially treatable cardiovascular disease in human patients with autosomal dominant LZTR1-Noonan syndrome and elucidate the differences in cardiac phenotypes between dominant and recessive forms of the disorder.<br /><br />Overall, this study provides initial insights into the phenotypic differences between mice with autosomal dominant and recessive LZTR1-Noonan syndrome and lays the groundwork for future investigations into potential treatments for cardiovascular complications associated with the disorder.
Asset Subtitle
Presenting Author - Corrine Capannari, Student; Co-Author - Kelly Smallwood, Bachelor of Science; Co-Author - Ronald Waclaw, PhD; Co-Author - Kathryn Nicole Weaver, MD;
Meta Tag
Cardiac/circulatory disorders
Genotype-Phenotype Correlations
Model Organisms
Phenotype
Co-Author
Kelly Smallwood, Bachelor of Science
Co-Author
Ronald Waclaw, PhD
Co-Author
Kathryn Nicole Weaver, MD
Presenting Author
Corrine Capannari, Student
Keywords
mouse model
autosomal dominant LZTR1-Noonan syndrome
genetic disorder
facial features
cardiac defects
short stature
developmental delay
missense allele
null allele
Kelch domains
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