Fmr1-KO Mouse

Fmr1, or Fragile X Messenger Ribonucleoprotein 1, is a gene that encodes the fragile X mental retardation protein (FMRP). FMRP is proposed to act as a regulator of mRNA transport and translation of target mRNAs at the synapse [7]. The gene is involved in pathways related to neurodevelopment and is of great biological importance as its abnormalities are associated with multiple disorders [3,7]. Genetic models, such as mouse models, can be valuable for studying Fmr1.

Fmr1 is associated with three main syndromes. Fragile X syndrome (FXS), the most common inherited form of intellectual disability, typically results from CGG-repeat expansions in the Fmr1 gene, leading to lack of expression [1,3,7,8]. Rare missense or nonsense mutations in Fmr1 can also cause FXS-like phenotypes [1]. In addition, expansions between 55-200 CGG repeats (premutation) are linked to Fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI) [4,5,6,7]. The elevated Fmr1 mRNA in FXTAS suggests a toxic RNA gain-of-function effect, while the molecular basis of FXPOI is unknown [7]. In FXS, Fmr1 RNA can be mis-spliced in a CGG expansion-dependent manner, and antisense oligonucleotide treatment may offer a therapeutic approach [2].

In conclusion, Fmr1 is crucial for normal neurodevelopment through its role in mRNA regulation at synapses. Studies related to Fmr1, especially those using gene knockout or other genetic models, have provided insights into the pathogenesis of FXS, FXTAS, and FXPOI. Understanding Fmr1's functions helps in exploring potential therapeutic strategies for these associated disorders.

References:

1. Sitzmann, Adam F, Hagelstrom, Robert T, Tassone, Flora, Hagerman, Randi J, Butler, Merlin G. 2017. Rare FMR1 gene mutations causing fragile X syndrome: A review. In American journal of medical genetics. Part A, 176, 11-18. doi:10.1002/ajmg.a.38504. https://pubmed.ncbi.nlm.nih.gov/29178241/

2. Shah, Sneha, Sharp, Kevin J, Raju Ponny, Sithara, Berry-Kravis, Elizabeth, Richter, Joel D. 2023. Antisense oligonucleotide rescue of CGG expansion-dependent FMR1 mis-splicing in fragile X syndrome restores FMRP. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2302534120. doi:10.1073/pnas.2302534120. https://pubmed.ncbi.nlm.nih.gov/37364131/

3. Gillett, Drew A, Tigro, Helene, Wang, Yuan, Suo, Zucai. 2024. FMR1 Disorders: Basics of Biology and Therapeutics in Development. In Cells, 13, . doi:10.3390/cells13242100. https://pubmed.ncbi.nlm.nih.gov/39768191/

4. Cao, Yiqu, Peng, Yun, Kong, Ha Eun, Allen, Emily G, Jin, Peng. 2020. Metabolic Alterations in FMR1 Premutation Carriers. In Frontiers in molecular biosciences, 7, 571092. doi:10.3389/fmolb.2020.571092. https://pubmed.ncbi.nlm.nih.gov/33195417/

5. Persico, Tiziana, Tranquillo, Maria Lucrezia, Seracchioli, Renato, Zuccarello, Daniela, Sorrentino, Ugo. 2023. PGT-M for Premature Ovarian Failure Related to CGG Repeat Expansion of the FMR1 Gene. In Genes, 15, . doi:10.3390/genes15010006. https://pubmed.ncbi.nlm.nih.gov/38275588/

6. Milà, Montserrat, Rodriguez-Revenga, Laia, Matilla-Dueñas, Antoni. . FMR1 Premutation: Basic Mechanisms and Clinical Involvement. In Cerebellum (London, England), 15, 543-5. doi:10.1007/s12311-016-0808-7. https://pubmed.ncbi.nlm.nih.gov/27338822/

7. Oostra, Ben A, Willemsen, Rob. 2009. FMR1: a gene with three faces. In Biochimica et biophysica acta, 1790, 467-77. doi:10.1016/j.bbagen.2009.02.007. https://pubmed.ncbi.nlm.nih.gov/19233246/

8. Mor-Shaked, Hagar, Eiges, Rachel. 2018. Reevaluation of FMR1 Hypermethylation Timing in Fragile X Syndrome. In Frontiers in molecular neuroscience, 11, 31. doi:10.3389/fnmol.2018.00031. https://pubmed.ncbi.nlm.nih.gov/29467618/