Flvcr1,全称为Feline Leukemia Virus subgroup C cellular receptor 1,是一种在哺乳动物中广泛表达的跨膜蛋白,属于主要易化超家族(Major Facilitator Superfamily)的溶质载体(SLC)转运蛋白。该基因编码两种亚型:FLVCR1a和FLVCR1b,分别定位于细胞质膜和线粒体,参与血红素、胆碱和乙醇胺的转运。Flvcr1基因的突变与多种疾病相关,包括Diamond-Blackfan贫血(DBA)、神经退行性疾病和先天性脑积水等。
研究发现,Flvcr1在哺乳动物中是一种主要的胆碱转运蛋白。当Flvcr1基因缺失时,胆碱代谢受损,导致胆碱的摄入受阻。此外,细胞和缺乏Flvcr1基因的小鼠表现出线粒体结构缺陷和整合应激反应(ISR)的激活。这些发现表明Flvcr1在胆碱代谢和线粒体功能中起着关键作用[1]。
缺氧条件下,Flvcr1基因的表达受到HIF2α和ETS1转录因子的调控。HIF2α和ETS1结合在Flvcr1启动子上,调控Flvcr1a亚型的转录。这一发现表明Flvcr1在缺氧诱导的生物学过程中,如红细胞生成、血管生成和血红素吸收中发挥重要作用[2]。
Flvcr1基因的突变与多种神经系统疾病相关,包括成年或晚发性的视网膜色素变性、脊髓和周围神经系统的神经退行性疾病。研究发现,Flvcr1突变导致胆碱和乙醇胺转运活性降低,影响神经发育和神经元稳态。此外,一些突变还影响mRNA的剪接,进一步影响Flvcr1的表达和功能[3,4,7]。
Flvcr1a亚型在神经前体细胞(NPCs)中与IP3R3-VDAC复合物相互作用,调节线粒体钙处理。缺乏Flvcr1a的NPCs表现出线粒体钙水平和能量代谢的紊乱,导致神经发生缺陷和脑室扩张,这是先天性脑积水(CH)的病理机制之一[5]。
此外,Flvcr1在磷脂酰胆碱(PC)代谢中也发挥重要作用。研究发现,Flvcr1作为胆碱摄取的促进剂,参与PC的合成和运输。通过流式细胞术和CRISPR筛选技术,研究人员发现Flvcr1在PC合成、囊泡膜转运和非囊泡转运中发挥重要作用[6]。
综上所述,Flvcr1基因在胆碱代谢、线粒体功能和神经系统发育中起着关键作用。Flvcr1的突变与多种疾病相关,包括DBA、神经退行性疾病和CH等。进一步研究Flvcr1的生物学功能和疾病发生机制,有助于为这些疾病的治疗和预防提供新的思路和策略。
参考文献:
1. Kenny, Timothy C, Khan, Artem, Son, Yeeun, Hite, Richard K, Birsoy, Kıvanç. 2023. Integrative genetic analysis identifies FLVCR1 as a plasma-membrane choline transporter in mammals. In Cell metabolism, 35, 1057-1071.e12. doi:10.1016/j.cmet.2023.04.003. https://pubmed.ncbi.nlm.nih.gov/37100056/
2. Fiorito, Veronica, Neri, Francesco, Pala, Valentina, Altruda, Fiorella, Tolosano, Emanuela. 2014. Hypoxia controls Flvcr1 gene expression in Caco2 cells through HIF2α and ETS1. In Biochimica et biophysica acta, 1839, 259-64. doi:10.1016/j.bbagrm.2014.02.010. https://pubmed.ncbi.nlm.nih.gov/24576667/
3. Sa'di, Qais, Alsmadi, Saba, Shtaiyat, Wanas, Qasaimeh, Mohammad, Munhoz, Renato P. 2024. FLVCR1 Gene Mutation in a Patient with an Atypical Multiple Sclerosis-Like Presentation. In The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, , 1-4. doi:10.1017/cjn.2024.351. https://pubmed.ncbi.nlm.nih.gov/39601177/
4. Calame, Daniel G, Wong, Jovi Huixin, Panda, Puravi, Lupski, James R, Nguyen, Long Nam. 2024. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders. In medRxiv : the preprint server for health sciences, , . doi:10.1101/2024.02.09.24302464. https://pubmed.ncbi.nlm.nih.gov/38405817/
5. Bertino, Francesca, Mukherjee, Dibyanti, Bonora, Massimo, Tolosano, Emanuela, Chiabrando, Deborah. . Dysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus. In Cell reports. Medicine, 5, 101647. doi:10.1016/j.xcrm.2024.101647. https://pubmed.ncbi.nlm.nih.gov/39019006/
6. Tsuchiya, Masaki, Tachibana, Nobuhiko, Nagao, Kohjiro, Tamura, Tomonori, Hamachi, Itaru. 2023. Organelle-selective click labeling coupled with flow cytometry allows pooled CRISPR screening of genes involved in phosphatidylcholine metabolism. In Cell metabolism, 35, 1072-1083.e9. doi:10.1016/j.cmet.2023.02.014. https://pubmed.ncbi.nlm.nih.gov/36917984/
7. Calame, Daniel G, Wong, Jovi Huixin, Panda, Puravi, Lupski, James R, Nguyen, Long N. 2024. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum. In Genetics in medicine : official journal of the American College of Medical Genetics, 27, 101273. doi:10.1016/j.gim.2024.101273. https://pubmed.ncbi.nlm.nih.gov/39306721/