Fmn1, a non-FDD-type Formin homology protein, plays a crucial role in multiple biological processes. It acts as an antagonist of the Bone Morphogenetic Protein (BMP) signaling pathway, especially during limb development. Fmn1 also has functions related to actin regulation, as it can interact with various proteins like Profilin, SRC, and FNBP4 [3,5].

Genomic rearrangements of the GREM1-FMN1 locus, including homozygous deletion of FMN1, are associated with oligosyndactyly, radioulnar synostosis, hearing loss, and renal defects, similar to the limb deformity (ld) phenotype in mice. A duplication encompassing both GREM1 and FMN1 genes was detected in a patient with isolated Cenani-Lenz-like oligosyndactyly [4]. Additionally, a genetic locus within the FMN1/GREM1 gene region interacts with body mass index (BMI) in colorectal cancer risk. Among participants with a specific CC genotype of rs58349661 in FMN1, overweight and obesity were associated with higher colorectal cancer risk [1]. In glioblastoma, the mechano-chemical-induced expression of FMN1 confers invasive strength [2]. In metastatic uveal melanoma, FMN1 was identified as a biomarker, with low expression associated with longer metastasis-free survival [6].

In summary, Fmn1 is essential in limb development through its role in the BMP pathway and actin regulation. Its genomic alterations and expression levels are associated with various disorders, including limb malformations, colorectal cancer, glioblastoma, and uveal melanoma. The study of Fmn1 in genetic models, such as the ld mouse model, has provided insights into the molecular mechanisms underlying these diseases, facilitating the understanding of disease pathogenesis and potentially guiding the development of new treatment strategies.

References:

1. Aglago, Elom K, Kim, Andre, Lin, Yi, Tsilidis, Konstantinos K, Campbell, Peter T. . A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk. In Cancer research, 83, 2572-2583. doi:10.1158/0008-5472.CAN-22-3713. https://pubmed.ncbi.nlm.nih.gov/37249599/

2. Monzo, Pascale, Crestani, Michele, Chong, Yuk Kien, Tang, Carol, Gauthier, Nils C. 2021. Adaptive mechanoproperties mediated by the formin FMN1 characterize glioblastoma fitness for invasion. In Developmental cell, 56, 2841-2855.e8. doi:10.1016/j.devcel.2021.09.007. https://pubmed.ncbi.nlm.nih.gov/34559979/

3. Katoh, Masuko, Katoh, Masaru. . Identification and characterization of the human FMN1 gene in silico. In International journal of molecular medicine, 14, 121-6. doi:. https://pubmed.ncbi.nlm.nih.gov/15202026/

4. Dimitrov, Boyan Ivanov, Voet, Thierry, De Smet, Luc, Fryns, Jean-Pierre, Debeer, Philippe. 2010. Genomic rearrangements of the GREM1-FMN1 locus cause oligosyndactyly, radio-ulnar synostosis, hearing loss, renal defects syndrome and Cenani--Lenz-like non-syndromic oligosyndactyly. In Journal of medical genetics, 47, 569-74. doi:10.1136/jmg.2009.073833. https://pubmed.ncbi.nlm.nih.gov/20610440/

5. Das, Shubham, Maiti, Sankar. 2023. Probing the ligand binding specificity of FNBP4 WW domains and interaction with FH1 domain of FMN1. In Current research in structural biology, 7, 100119. doi:10.1016/j.crstbi.2023.100119. https://pubmed.ncbi.nlm.nih.gov/38188541/

6. Wang, Tan, Wang, Zixing, Yang, Jingyuan, Chen, Youxin, Min, Hanyi. 2022. Screening and Identification of Key Biomarkers in Metastatic Uveal Melanoma: Evidence from a Bioinformatic Analysis. In Journal of clinical medicine, 11, . doi:10.3390/jcm11237224. https://pubmed.ncbi.nlm.nih.gov/36498797/