Mfsd8-KO Mouse

MFSD8, also known as CLN7, is a transmembrane protein reported to function as a lysosomal chloride channel [2]. It has been associated with the regulation of conserved processes during the life cycle of the social amoeba Dictyostelium discoideum [2]. In humans, it is involved in neuronal ceroid lipofuscinosis (NCL) diseases, highlighting its importance in human health [2,3,5,7,9]. Genetic models like Dictyostelium discoideum help in studying its functions [2,5,7].

Mutations in MFSD8 can cause type 7 neuronal ceroid lipofuscinosis, leading to vision loss and other systemic symptoms [1]. It can also cause isolated retinal dystrophy or non-syndromic macular dystrophy without systemic signs [1,3,8]. In Dictyostelium, loss of mfsd8 deregulates protein secretion, affects proteasome activity, and impacts the organism's development, including growth, pinocytosis, and aggregation [2,5]. In Mfsd8-/-mice, AAV9/MFSD8 gene therapy shows age-and dose-dependent effects, improving various disease-related phenotypes [4]. In a CLN7-deficient HEK293T cell line, the viral load of SARS-CoV-2 is reduced, indicating MFSD8's potential role in the virus's cell entry [6].

In summary, MFSD8 is crucial for normal physiological functions, especially related to lysosomal function, protein secretion, and cell-related processes. Model-based research, such as in Dictyostelium and Mfsd8-/-mice, has revealed its role in diseases like neuronal ceroid lipofuscinosis, retinal dystrophies, and potentially in SARS-CoV-2 infection. Understanding MFSD8 provides insights into disease mechanisms and potential therapeutic targets for these associated diseases.

References:

1. Priluck, Aaron Z, Breazzano, Mark P. 2022. Novel MFSD8 mutation causing non-syndromic asymmetric adult-onset macular dystrophy. In Ophthalmic genetics, 44, 186-190. doi:10.1080/13816810.2022.2092758. https://pubmed.ncbi.nlm.nih.gov/35801630/

2. Huber, Robert J, Gray, Joshua, Kim, William D. 2023. Loss of mfsd8 alters the secretome during Dictyostelium aggregation. In European journal of cell biology, 102, 151361. doi:10.1016/j.ejcb.2023.151361. https://pubmed.ncbi.nlm.nih.gov/37742391/

3. Zare-Abdollahi, Davood, Bushehri, Ata, Alavi, Afagh, Jamali, Payman, Khorram Khorshid, Hamid Reza. 2019. MFSD8 gene mutations; evidence for phenotypic heterogeneity. In Ophthalmic genetics, 40, 141-145. doi:10.1080/13816810.2019.1592200. https://pubmed.ncbi.nlm.nih.gov/31006324/

4. Chen, Xin, Dong, Thomas, Hu, Yuhui, Mazzulli, Joseph R, Gray, Steven J. . AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease. In The Journal of clinical investigation, 132, . doi:10.1172/JCI146286. https://pubmed.ncbi.nlm.nih.gov/35025759/

5. Yap, Shyong Quan, Kim, William D, Huber, Robert J. 2022. Mfsd8 Modulates Growth and the Early Stages of Multicellular Development in Dictyostelium discoideum. In Frontiers in cell and developmental biology, 10, 930235. doi:10.3389/fcell.2022.930235. https://pubmed.ncbi.nlm.nih.gov/35756993/

6. Heinl, Elena-Sofia, Lorenz, Sebastian, Schmidt, Barbara, Wetzel, Christian H, Reichold, Markus. 2022. CLN7/MFSD8 may be an important factor for SARS-CoV-2 cell entry. In iScience, 25, 105082. doi:10.1016/j.isci.2022.105082. https://pubmed.ncbi.nlm.nih.gov/36093380/

7. Huber, Robert J, Mathavarajah, Sabateeshan, Yap, Shyong Quan. 2020. Mfsd8 localizes to endocytic compartments and influences the secretion of Cln5 and cathepsin D in Dictyostelium. In Cellular signalling, 70, 109572. doi:10.1016/j.cellsig.2020.109572. https://pubmed.ncbi.nlm.nih.gov/32087303/

8. Xiang, Qin, Cao, Yanna, Xu, Hongbo, Deng, Hao, Yuan, Lamei. 2021. Novel MFSD8 Variants in a Chinese Family with Nonsyndromic Macular Dystrophy. In Journal of ophthalmology, 2021, 6684045. doi:10.1155/2021/6684045. https://pubmed.ncbi.nlm.nih.gov/34457359/

9. Qiao, Yimeng, Gu, Yang, Cheng, Ye, Shang, Qing, Xing, Qinghe. 2022. Case Report: Novel MFSD8 Variants in a Chinese Family With Neuronal Ceroid Lipofuscinoses 7. In Frontiers in genetics, 13, 807515. doi:10.3389/fgene.2022.807515. https://pubmed.ncbi.nlm.nih.gov/35154277/