GXYLT1, a member of the glycosyltransferase 8 family, functions as a xylosyltransferase acting on O-glucosylated EGF repeats of Notch [9]. It is involved in the xylosyl elongation of O-glucose, which has significance in the quality control of Notch receptors, regulating their cell-surface trafficking [6]. NOTCH activation can promote the expression of GXYLT1 in human myeloid leukemia cells, suggesting a role in modulating NOTCH sensitivity through increased glycosylation of NOTCH receptors [5].

Genetic analysis of 45 CRC patients in northern China by whole-exome sequencing revealed GXYLT1 was mutated in 40% of samples. Functionally, GXYLT1 promoted migration, invasion in vitro and metastasis in vivo. The GXYLT1S212* mutant had a more significant effect, mainly promoting metastasis by activating the MAPK pathway. GXYLT1 may act as a novel metastasis-associated driver gene in CRC [1]. In Crohn disease, exome sequencing implicated GXYLT1 in modulating granuloma formation, with potential subgroup associations [2]. In psoriasis, GXYLT1 mutations were identified, potentially selected for in squamous epithelium regardless of disease status [3]. A genome-wide meta-analysis found a genetic variant near GXYLT1 associated with glycemic response to sulfonylureas, with the C allele at rs1234032 associated with less HbA1c reduction and higher glucose trough levels, and also being a cis eQTL for increased GXYLT1 expression [4]. In the study of carotid paragangliomas and Cronkhite-Canada syndrome, GXYLT1 was among the genes potentially associated with their development [7,8].

In summary, GXYLT1 has important functions in glycosylation and Notch-related processes. Its role in various diseases such as CRC, Crohn disease, psoriasis, and in glycemic response to sulfonylureas, as well as its potential association with carotid paragangliomas and Cronkhite-Canada syndrome, has been revealed through genetic and functional studies. Understanding GXYLT1 may provide insights into disease mechanisms and potential therapeutic targets.