Fmr1, or Fragile X Messenger Ribonucleoprotein 1, is a gene that plays a crucial role in regulating mRNA transport and translation of target mRNAs at the synapse [4]. It is involved in three different syndromes: fragile X syndrome (FXS), premature ovarian insufficiency (POI), and fragile X-associated tremor/ataxia syndrome (FXTAS) [4]. FXS is caused by a CGG-repeat expansion above 200 units in the Fmr1 gene, leading to the absence of Fmr1 mRNA and protein, representing a loss-of-function disorder [4]. POI and FXTAS are associated with an expanded repeat between 50-200 CGGs and increased Fmr1 mRNA levels, with FXTAS potentially being a toxic RNA gain-of-function effect [4].

Fmr1 mutations, such as the rare missense mutation (c.413G>A), can also cause FXS-like phenotypes without the typical CGG-repeat expansion [1]. In FXS, aberrant alternative splicing of Fmr1 mRNA occurs, generating the FMR1-217 RNA isoform, and antisense oligonucleotide treatment can rescue full-length Fmr1 RNA and restore FMRP (the protein encoded by Fmr1) [2]. Fmr1 premutation carriers are at risk of developing FXTAS and FXPOI, and recent metabolic studies in these carriers may provide insights into potential biomarkers and therapeutic pathways [3].

In conclusion, Fmr1 is essential for normal synaptic function, and its dysregulation through mutations or repeat expansions is associated with multiple disorders including FXS, POI, and FXTAS. Studies on Fmr1-related disorders help understand the gene's role in these diseases, potentially leading to the development of new therapeutic strategies for these conditions [1,2,3,4].

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. 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/

4. 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/