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Updated: Nov 9, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy
Tirtha K Das1,2, Jared Gatto1,2, Rupa Mirmira1
1Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York NY, USA.
Abstract:
RASopathies represent a family of mostly autosomal dominant diseases that are caused by missense variants in the rat sarcoma viral oncogene/mitogen activated protein kinase (RAS/MAPK) pathway including KRAS, NRAS, BRAF, RAF1, and SHP2. These variants are associated with overlapping but distinct phenotypes that affect the heart, craniofacial, skeletal, lymphatic, and nervous systems. Here, we report an analysis of 13 Drosophila transgenic lines, each expressing a different human RASopathy isoform. Similar to their human counterparts, each Drosophila line displayed common aspects but also important differences including distinct signaling pathways such as the Hippo and SAPK/JNK signaling networks. We identified multiple classes of clinically relevant drugs-including statins and histone deacetylase inhibitors-that improved viability across most RASopathy lines; in contrast, several canonical RAS pathway inhibitors proved less broadly effective. Overall, our study compares and contrasts a large number of RASopathy-associated variants including their therapeutic responses.
Insights
RASopathies, genetic disorders affecting multiple systems, were studied in Drosophila models. Statins and HDAC inhibitors showed therapeutic potential, outperforming canonical RAS pathway drugs.
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Pharmacology
Background:
- RASopathies are a group of genetic disorders caused by variants in the RAS/MAPK pathway.
- These conditions manifest with diverse phenotypes impacting multiple organ systems.
- Understanding these complex diseases requires robust model systems.
Purpose of the Study:
- To analyze the impact of various RASopathy-associated human variants using Drosophila models.
- To compare the distinct signaling pathways affected by different RASopathy isoforms.
- To identify potential therapeutic strategies for RASopathies.
Main Methods:
- Generation and analysis of 13 Drosophila transgenic lines, each expressing a distinct human RASopathy isoform.
- Comparative analysis of phenotypes and affected signaling pathways (e.g., Hippo, SAPK/JNK).
- Screening of clinically relevant drugs for their efficacy in improving RASopathy model viability.
Main Results:
- Drosophila models recapitulated common and distinct features of human RASopathies.
- Significant differences in affected signaling pathways were observed among different RASopathy lines.
- Statins and histone deacetylase inhibitors demonstrated broad efficacy in improving viability across models.
- Canonical RAS pathway inhibitors showed limited effectiveness.
Conclusions:
- Drosophila serves as a valuable model for studying RASopathies and their associated signaling networks.
- Repurposed drugs like statins and HDAC inhibitors offer promising therapeutic avenues for RASopathies.
- Therapeutic strategies need to consider the specific molecular underpinnings of individual RASopathy variants.
