Best1-KO Mouse

Best1, also known as Bestrophin-1, is a calcium-activated anion channel. It is expressed in various tissues including the retinal pigment epithelium (RPE) and the brain [2]. In the RPE, it is involved in maintaining the normal function of the retina, and mutations in the BEST1 gene can lead to bestrophinopathy, a retinal disorder [1,3,4,5,6]. In the brain, it has a significant permeability to glutamate and GABA, which are important neurotransmitters, and is involved in modulating neuronal excitability, synaptic transmission, and synaptic plasticity [2]. Genetic models, such as pluripotent stem cell-derived RPE cells expressing mutant BEST1, can be used to study the influences of BEST1 mutations on its physiological function [6].

Mutations in the BEST1 gene have been associated with various retinal degenerative disorders, collectively called bestrophinopathies. These include autosomal dominant bestrophinopathies (VMD) and autosomal recessive bestrophinopathies (ARB). Different BEST1 mutations result in distinct phenotypic diversity, even within families [5]. In Japanese siblings with ARB, a novel BEST1 mutation was identified, and the associated clinical features included multifocal yellowish subretinal deposits, cystoid macular edema, and subretinal fluid [4]. In Chinese families, novel BEST1 variants were found in both VMD and ARB families, with intrafamilial phenotypic diversity observed [5]. Unilateral BEST1-associated retinopathy has also been reported, where the reduced electrooculogram light rise was bilateral despite unilateral clinical manifestation, indicating generalized RPE dysfunction [3].

In conclusion, Best1 is crucial for normal retinal and brain function. Through model-based research, we've learned that mutations in the BEST1 gene can lead to various bestrophinopathies with diverse phenotypes. Understanding the role of Best1 in these disease conditions can potentially contribute to the development of gene and cell-based therapies for retinal disorders [1,6].

References:

1. Yang, Tingting, Justus, Sally, Li, Yao, Tsang, Stephen H. 2015. BEST1: the Best Target for Gene and Cell Therapies. In Molecular therapy : the journal of the American Society of Gene Therapy, 23, 1805-9. doi:10.1038/mt.2015.177. https://pubmed.ncbi.nlm.nih.gov/26388462/

2. Oh, Soo-Jin, Lee, C Justin. 2017. Distribution and Function of the Bestrophin-1 (Best1) Channel in the Brain. In Experimental neurobiology, 26, 113-121. doi:10.5607/en.2017.26.3.113. https://pubmed.ncbi.nlm.nih.gov/28680296/

3. Arora, Rashi, Khan, Kamron, Kasilian, Melissa L, Moore, Anthony T, Michaelides, Michel. 2016. Unilateral BEST1-Associated Retinopathy. In American journal of ophthalmology, 169, 24-32. doi:10.1016/j.ajo.2016.05.024. https://pubmed.ncbi.nlm.nih.gov/27287821/

4. Yamada, Rika, Takagi, Rina, Iwamoto, Sadahiko, Shimada, Shoichi, Kakehashi, Akihiro. 2021. Novel BEST1 mutation in autosomal recessive bestrophinopathy in Japanese siblings. In Taiwan journal of ophthalmology, 11, 71-76. doi:10.4103/tjo.tjo_37_20. https://pubmed.ncbi.nlm.nih.gov/33767958/

5. Yang, Shangying, Li, Zhen, Cheng, Wanyu, Sheng, Xunlun, Rong, Weining. 2022. BEST1 novel mutation causes Bestrophinopathies in six families with distinct phenotypic diversity. In Molecular genetics & genomic medicine, 11, e2095. doi:10.1002/mgg3.2095. https://pubmed.ncbi.nlm.nih.gov/36378562/

6. Kittredge, Alec, Zhang, Yu, Yang, Tingting. 2021. Evaluating BEST1 mutations in pluripotent stem cell-derived retinal pigment epithelial cells. In Methods in enzymology, 654, 365-382. doi:10.1016/bs.mie.2021.01.004. https://pubmed.ncbi.nlm.nih.gov/34120722/