FRG1, short for FSHD region gene 1, is the primary candidate gene for Fascioscapulohumeral Muscular Dystrophy (FSHD). It has been implicated in multiple physiological processes. Mechanistically, it may play a role in RNA biogenesis, influencing pathways like mRNA surveillance, RNA transport, and spliceosome machinery [1]. It is also associated with processes such as muscle development, vasculogenesis, angiogenesis, and tumorigenesis [1,2,3,4,5,6,7,8]. Genetic models, like those in Xenopus laevis and mouse myoblasts, have been valuable in studying its functions [7,9].

In terms of specific findings, in Xenopus laevis, frg1 is expressed in and essential for tadpole musculature development. Disrupting its expression led to myotome organization and growth defects, while overexpression caused abnormal muscle formation, suggesting its crucial role in proper muscle development [7]. In mouse myoblasts overexpressing FRG1, decreased proliferation was observed, which may contribute to the pathology of FSHD [9]. In cancer studies, reduced FRG1 expression promoted angiogenesis via the FGF2-mediated ERK/AKT pathway in breast cancer [2], and in prostate cancer, it affected cell migration and invasion, likely through p38 MAPK activation [4]. FRG1 also seems to play a role in DNA repair in breast cancer, with low expression associated with reduced DNA repair capabilities and a higher frequency of TP53 mutation [3].

In conclusion, FRG1 is vital for muscle development and has significant implications in angiogenesis, tumorigenesis, and DNA repair. Studies using genetic models, especially in muscle-related and cancer-related disease areas, have revealed its multifaceted functions. Understanding FRG1 can potentially provide insights into the pathophysiology of FSHD and cancer, offering new directions for therapeutic strategies.

References:

1. Palo, Ananya, Patel, Saket Awadhesbhai, Sahoo, Bibekananda, Chowdary, Tirumala Kumar, Dixit, Manjusha. 2022. FRG1 is a direct transcriptional regulator of nonsense-mediated mRNA decay genes. In Genomics, 115, 110539. doi:10.1016/j.ygeno.2022.110539. https://pubmed.ncbi.nlm.nih.gov/36521634/

2. Mukherjee, Bratati, Brahma, Pratush, Mohapatra, Talina, Chawla, Saurabh, Dixit, Manjusha. 2023. Reduced FRG1 expression promotes angiogenesis via activation of the FGF2-mediated ERK/AKT pathway. In FEBS open bio, 13, 804-817. doi:10.1002/2211-5463.13582. https://pubmed.ncbi.nlm.nih.gov/36815234/

3. Shubhanjali, Shubhanjali, Mohapatra, Talina, Khan, Rehan, Dixit, Manjusha. 2024. Unveiling FRG1's DNA repair role in breast cancer. In Scientific reports, 14, 19371. doi:10.1038/s41598-024-70368-9. https://pubmed.ncbi.nlm.nih.gov/39169067/

4. Tiwari, Ankit, Mukherjee, Bratati, Hassan, Md Khurshidul, Jaiswal, Archita Mohanty, Dixit, Manjusha. 2019. Reduced FRG1 expression promotes prostate cancer progression and affects prostate cancer cell migration and invasion. In BMC cancer, 19, 346. doi:10.1186/s12885-019-5509-4. https://pubmed.ncbi.nlm.nih.gov/30975102/

5. Mukherjee, Bratati, Tiwari, Ankit, Palo, Ananya, Samantara, Subrat, Dixit, Manjusha. 2022. Reduced expression of FRG1 facilitates breast cancer progression via GM-CSF/MEK-ERK axis by abating FRG1 mediated transcriptional repression of GM-CSF. In Cell death discovery, 8, 442. doi:10.1038/s41420-022-01240-w. https://pubmed.ncbi.nlm.nih.gov/36329016/

6. DeSimone, Alec M, Pakula, Anna, Lek, Angela, Emerson, Charles P. 2017. Facioscapulohumeral Muscular Dystrophy. In Comprehensive Physiology, 7, 1229-1279. doi:10.1002/cphy.c160039. https://pubmed.ncbi.nlm.nih.gov/28915324/

7. Hanel, Meredith L, Wuebbles, Ryan D, Jones, Peter L. . Muscular dystrophy candidate gene FRG1 is critical for muscle development. In Developmental dynamics : an official publication of the American Association of Anatomists, 238, 1502-12. doi:10.1002/dvdy.21830. https://pubmed.ncbi.nlm.nih.gov/19097195/

8. Hansda, Arman Kunwar, Tiwari, Ankit, Dixit, Manjusha. . Current status and future prospect of FSHD region gene 1. In Journal of biosciences, 42, 345-353. doi:. https://pubmed.ncbi.nlm.nih.gov/28569257/

9. Chen, Steven C, Frett, Ellie, Marx, Joseph, Kyba, Michael, Kennedy, Brian K. 2011. Decreased proliferation kinetics of mouse myoblasts overexpressing FRG1. In PloS one, 6, e19780. doi:10.1371/journal.pone.0019780. https://pubmed.ncbi.nlm.nih.gov/21603621/