Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy.
Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy.
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DOI：
10.1016/j.isci.2021.102306
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发表时间：
2021-04-23
期刊：
影响因子：
5.8
通讯作者：
Cagan R
中科院分区：
文献类型：
--
作者：
Das TK;Gatto J;Mirmira R;Hourizadeh E;Kaufman D;Gelb BD;Cagan R
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. Patients with RASopathy present with variable symptoms and have poor therapeutic options We established 13 Drosophila models, each expressing a human RASopathy variant Models displayed variability in deregulated pathways, mirroring human heterogeneity Screening identified drug classes broadly active across RASopathy subtypes Biological Sciences; Physiology; Molecular Biology; Cell Biology
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影响因子：
4.8
作者：
Eminaga, Seda;Bennett, Anton M.
通讯作者：
Bennett, Anton M.
影响因子：
8
作者：
Azad, Taha;Nouri, Kazem;Yang, Xiaolong
通讯作者：
Yang, Xiaolong
影响因子：
4.8
作者：
Bichsel, SJ;Tamaskovic, R;Hemmings, BA
通讯作者：
Hemmings, BA
影响因子：
3.9
作者：
Cordeddu, Viviana;Yin, Jiani C.;Tartaglia, Marco
通讯作者：
Tartaglia, Marco
影响因子：
6.2
作者：
Das, T. K.;Dana, D.;Paroly, S. S.;Perumal, S. K.;Singh, S.;Jhun, H.;Pendse, J.;Cagan, R. L.;Talele, T. T.;Kumar, S.
通讯作者：
Kumar, S.