Slc66a1-KO Mouse

Slc66a1, also known as PQLC2, is a lysosomal cationic amino acid transporter [2,3,5,6]. It plays a crucial role in maintaining amino acid homeostasis, transporting lysine, arginine, and histidine across the lysosomal membrane [2,3,6]. PQLC2 is also involved in the lysosomal sensing of cationic amino acids, as it can recruit a protein complex composed of C9orf72, SMCR8, and WDR41 to the surface of lysosomes in response to substrate scarcity, which controls multiple aspects of lysosome function [2].

In terms of disease associations, studies have identified homozygous pathogenic variants in SLC66A1, causing autosomal recessive retinitis pigmentosa (ARRP), suggesting it as a candidate novel gene for inherited retinal diseases [1]. Additionally, it has been proposed as a likely novel cause for autosomal recessive rod-cone dystrophy in 4 families based on copy-number analysis of genome sequencing data [4]. In gastric cancer, upregulation of PQLC2 was critical to cancer development in vitro and in vivo, promoting cell growth, anchorage independence, and tumor formation, indicating it as a potential therapeutic target [5].

In conclusion, Slc66a1 (PQLC2) is essential for lysosomal cationic amino acid transport and sensing, playing a significant role in maintaining normal cellular function. Its association with autosomal recessive retinal diseases and gastric cancer, as revealed through genetic studies, highlights its importance in understanding the pathogenesis of these diseases and potentially developing targeted therapies.

References:

1. Millo, Talya, Rivera, Antonio, Obolensky, Alexey, Banin, Eyal, Sharon, Dror. 2022. Identification of autosomal recessive novel genes and retinal phenotypes in members of the solute carrier (SLC) superfamily. In Genetics in medicine : official journal of the American College of Medical Genetics, 24, 1523-1535. doi:10.1016/j.gim.2022.03.020. https://pubmed.ncbi.nlm.nih.gov/35486108/

2. Talaia, Gabriel, Amick, Joseph, Ferguson, Shawn M. . Receptor-like role for PQLC2 amino acid transporter in the lysosomal sensing of cationic amino acids. In Proceedings of the National Academy of Sciences of the United States of America, 118, . doi:10.1073/pnas.2014941118. https://pubmed.ncbi.nlm.nih.gov/33597295/

3. Amick, Joseph, Tharkeshwar, Arun Kumar, Talaia, Gabriel, Ferguson, Shawn M. . PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation. In The Journal of cell biology, 219, . doi:10.1083/jcb.201906076. https://pubmed.ncbi.nlm.nih.gov/31851326/

4. Olinger, Eric, Wilson, Ian J, Orr, Sarah, Atan, Denize, Sayer, John A. 2024. Copy-number analysis from genome sequencing data of 11,754 rare-disease parent-child trios: A model for identifying autosomal recessive human gene knockouts including a novel gene for autosomal recessive retinopathy. In Genetics in medicine open, 2, 101834. doi:10.1016/j.gimo.2024.101834. https://pubmed.ncbi.nlm.nih.gov/39669628/

5. Jeung, Yun-Ji, Lee, Kyeong, Lee, Hyo Jin, Kim, Jin Man, Chung, Kyung-Sook. 2019. Cationic amino acid transporter PQLC2 is a potential therapeutic target in gastric cancer. In Cancer science, 110, 1453-1463. doi:10.1111/cas.13966. https://pubmed.ncbi.nlm.nih.gov/30729615/

6. Jézégou, Adrien, Llinares, Elisa, Anne, Christine, André, Bruno, Gasnier, Bruno. 2012. Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy. In Proceedings of the National Academy of Sciences of the United States of America, 109, E3434-43. doi:10.1073/pnas.1211198109. https://pubmed.ncbi.nlm.nih.gov/23169667/