A comprehensive functional analysis of Dup15q ‎genes: phenotypic effects and treatment ‎following restoration‎

Awardee: Alon Zaslaver

Institution: The Hebrew University

Grant Amount: $47,038

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

Dup15q syndrome is genetically inherited and is caused due to an extra copy of a piece of ‎chromosome ‎‎15. As a results, the genes located on that chromosome region are expressed at ‎higher levels. However, ‎it is less clear which genes contribute to the various observed deficits. ‎Moreover, unless genetically tested during pregnancy, children with Dup15q are typically ‎‎diagnosed only at the age of ~2 years old. Thus, new therapeutic approaches need to focus on ‎‎improving and restoring functional deficits after most embryonic neurodevelopmental processes ‎are complete.‎ To address all these needs, we will use the powerful genetic model system (C. elegans worms). ‎Specifically, we ‎carefully designed an experimental genetic system which allows mild and fine ‎upregulation of individual and combinations of Dup15q genes during neurodevelopment, and ‎restoration of the elevated expression to normal ‎levels at the adult stage of the animal. To ‎analyze neurodevelopmental deficits, we will ‎use state-of-the-art experimental techniques ‎including functional imaging of neural activity and behavioral ‎assays.‎ These efforts will reveal the individual and sets of genes that lead to neurodevelopmental ‎phenotypes, and most importantly, whether restoration of gene expression to normal levels,‎ can improve these phenotypic deficits. Such findings may pave the way to novel interventions ‎and ‎therapeutic approaches.‎

Deep phenotyping of mouse models of UBE3A gain-of-function

Awardee: Jason Yi

Institution: Washington University School of Medicine

Grant Amount: $47,158.00

Funding Period: February 1, 2024 - January 31, 2025

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Summary:

Dup15q syndrome is caused by a duplication or triplication of maternal chromosome 15q11-13 whereas individuals with paternal duplications are typically developing. There are more than 20 genes within chromosome 15q11-13, but among them, Ube3a is the only gene expressed exclusively from the maternal allele in neurons. These observations strongly suggest that excessive UBE3A protein activity is the major driver of disease phenotypes in Dup15q syndrome. This proposal will perform deep phenotypic analysis of an allelic series of mice that possess gain-of-function mutations in Ube3a of increasing severity. By doing so, our study will identify specific phenotypes in mice that are caused by excessive UBE3A protein activity. These studies will provide valuable models and information that can be leveraged to design therapeutic strategies for this disorder.