GXYLT1, a gene encoding a xylosyltransferase, is involved in glycosylation processes, specifically acting on O-glucosylated EGF repeats of Notch [7]. Glycosylation is crucial for many biological processes, and GXYLT1-mediated glycosylation may impact protein functions, cell-cell interactions, and signaling pathways like Notch [5,7]. Genetic models could potentially offer insights into its function in normal and disease states.

In colorectal cancer, GXYLT1 was mutated in 40% of samples from a cohort. Functionally, it promoted migration, invasion in vitro and metastasis in vivo, with the GXYLT1S212* mutant having a more significant effect. GXYLT1 interacted with ERK2 and induced metastasis via the Notch and MAPK pathways, while the GXYLT1S212* mutant mainly activated the MAPK pathway, suggesting it as a novel metastasis-associated driver gene [1]. In Crohn's disease, exome sequencing implicated GXYLT1 in modulating granuloma formation [2]. In psoriasis, mutations in GXYLT1 were found in keratinocytes, hypothesized to be selected for in squamous epithelium regardless of disease status [3]. Genome-wide meta-analysis associated a genetic variant near GXYLT1 with glycemic response to sulfonylureas, and the C allele at rs1234032 was a cis-eQTL for increased GXYLT1 expression [4]. NOTCH activation promoted GXYLT1 expression in human myeloid leukemia cells [5]. Whole exome sequencing of carotid paragangliomas revealed GXYLT1 as potentially associated with tumor initiation and progression [6]. In rheumatoid arthritis, differential GXYLT1 expression was noted between non-erosive and erosive seropositive cases [8]. A two-sample Mendelian randomization study suggested a possible connection between GXYLT1 and hypertension [9].

In summary, GXYLT1 is involved in multiple biological processes and disease conditions. Through various research, it has been linked to metastasis in colorectal cancer, granuloma formation in Crohn's disease, keratinocyte mutations in psoriasis, glycemic response to sulfonylureas, myeloid leukemia cell regulation, carotid paraganglioma development, and potentially erosive phenotypes in rheumatoid arthritis and hypertension. These findings from different disease-related studies using various research models contribute to understanding the diverse functions of GXYLT1 in human health and disease.

References:

1. Peng, Lin, Zhao, Min, Liu, Tianqi, Jiang, Beihai, Su, Xiangqian. 2022. A stop-gain mutation in GXYLT1 promotes metastasis of colorectal cancer via the MAPK pathway. In Cell death & disease, 13, 395. doi:10.1038/s41419-022-04844-3. https://pubmed.ncbi.nlm.nih.gov/35459861/

2. Harris, R Alan, Bush, Allyson H, Eagar, Todd N, Kugathasan, Subra, Kellermayer, Richard. 2023. Exome Sequencing Implicates DGKZ , ESRRA , and GXYLT1 for Modulating Granuloma Formation in Crohn Disease. In Journal of pediatric gastroenterology and nutrition, 77, 354-357. doi:10.1097/MPG.0000000000003873. https://pubmed.ncbi.nlm.nih.gov/37347142/

3. Olafsson, Sigurgeir, Rodriguez, Elke, Lawson, Andrew R J, Campbell, Peter J, Anderson, Carl A. 2023. Effects of psoriasis and psoralen exposure on the somatic mutation landscape of the skin. In Nature genetics, 55, 1892-1900. doi:10.1038/s41588-023-01545-1. https://pubmed.ncbi.nlm.nih.gov/37884686/

4. Dawed, Adem Y, Yee, Sook Wah, Zhou, Kaixin, Giacomini, Kathleen M, Pearson, Ewan R. 2021. Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas. In Diabetes care, 44, 2673-2682. doi:10.2337/dc21-1152. https://pubmed.ncbi.nlm.nih.gov/34607834/

5. Wang, Shichun, Itoh, Mai, Shiratori, Erika, Ohtaka, Mika, Tohda, Shuji. 2018. NOTCH activation promotes glycosyltransferase expression in human myeloid leukemia cells. In Hematology reports, 10, 7576. doi:10.4081/hr.2018.7576. https://pubmed.ncbi.nlm.nih.gov/30344988/

6. Snezhkina, A V, Lukyanova, E N, Fedorova, M S, Pudova, E A, Kudryavtseva, A V. . [Novel Genes Associated with the Development of Carotid Paragangliomas]. In Molekuliarnaia biologiia, 53, 613-626. doi:10.1134/S0026898419040141. https://pubmed.ncbi.nlm.nih.gov/31397435/

7. Sethi, Maya K, Buettner, Falk F R, Ashikov, Angel, Bakker, Hans. . In vitro assays of orphan glycosyltransferases and their application to identify Notch xylosyltransferases. In Methods in molecular biology (Clifton, N.J.), 1022, 307-20. doi:10.1007/978-1-62703-465-4_23. https://pubmed.ncbi.nlm.nih.gov/23765671/

8. Hoang Dong, Nguyen, Audrey, Lortie, Leopold, Mbous Nguimbus, Scott, Michelle S, Sophie, Roux. 2023. Osteoclast microRNA Profiling in Rheumatoid Arthritis to Capture the Erosive Factor. In JBMR plus, 7, e10776. doi:10.1002/jbm4.10776. https://pubmed.ncbi.nlm.nih.gov/37614303/

9. Li, Jin, Yao, Yue-Xian, Yao, Pei-Sen. 2023. Circulating Biomarkers and Risk of Hypertension: A Two-Sample Mendelian Randomisation Study. In Heart, lung & circulation, 32, 1434-1442. doi:10.1016/j.hlc.2023.09.003. https://pubmed.ncbi.nlm.nih.gov/38042639/