Stx1a, also found as a subtype in Shiga toxin, consists of two major subunits. The A subunit injures the eukaryotic ribosome and halts protein synthesis, while the B pentamer binds to the cellular receptor, globotriaosylceramide (Gb3), mainly on endothelial cells. It is involved in the pathogenesis of diseases caused by Shiga toxin-producing bacteria, like Escherichia coli-related hemolytic-uremic syndrome [3].

In human genetic studies, ultra-rare variants in STX1A are associated with a neurodevelopmental disorder. Missense variants may lead to an STX1A-related developmental epileptic encephalopathy due to weakened inhibitory STX1A-STXBP1 interaction, while in-frame deletions cause an STX1A-related intellectual disability and autism phenotype by hampering SNARE complex formation [1]. In addition, STX1A gene variations contribute to the susceptibility of children with attention-deficit/hyperactivity disorder (ADHD), as certain single nucleotide polymorphisms (SNPs) are associated with the risk and clinical characteristics of ADHD [2]. The gene has also been linked to Asperger syndrome, with some SNPs showing significant associations [5]. In gastric cancer, STX1A overexpression is observed, and its knockdown can inhibit cell proliferation and induce ferroptosis, potentially reversing chemoresistance [4].

In conclusion, Stx1a plays diverse roles, from being a key virulence factor in bacterial-related diseases to having implications in various neurodevelopmental disorders and cancer. The study of its genetic variants in human populations helps in understanding the underlying disease mechanisms, providing potential targets for diagnosis and treatment in these disease areas.

References:

1. Luppe, Johannes, Sticht, Heinrich, Lecoquierre, François, Abou Jamra, Rami, Platzer, Konrad. 2022. Heterozygous and homozygous variants in STX1A cause a neurodevelopmental disorder with or without epilepsy. In European journal of human genetics : EJHG, 31, 345-352. doi:10.1038/s41431-022-01269-6. https://pubmed.ncbi.nlm.nih.gov/36564538/

2. Wang, Min, Gu, Xue, Huang, Xin, Chen, Xinzhen, Wu, Jing. 2019. STX1A gene variations contribute to the susceptibility of children attention-deficit/hyperactivity disorder: a case-control association study. In European archives of psychiatry and clinical neuroscience, 269, 689-699. doi:10.1007/s00406-019-01010-3. https://pubmed.ncbi.nlm.nih.gov/30976917/

3. Melton-Celsa, Angela R. . Shiga Toxin (Stx) Classification, Structure, and Function. In Microbiology spectrum, 2, EHEC-0024-2013. doi:10.1128/microbiolspec.EHEC-0024-2013. https://pubmed.ncbi.nlm.nih.gov/25530917/

4. Niu, Yan, Liu, Chunyu, Jia, Lizhou, Gan, Yanzi, Wen, Yongjun. 2025. STX1A regulates ferroptosis and chemoresistance in gastric cancer through mitochondrial function modulation. In Human cell, 38, 66. doi:10.1007/s13577-025-01195-x. https://pubmed.ncbi.nlm.nih.gov/40056239/

5. Durdiaková, Jaroslava, Warrier, Varun, Banerjee-Basu, Sharmila, Baron-Cohen, Simon, Chakrabarti, Bhismadev. 2014. STX1A and Asperger syndrome: a replication study. In Molecular autism, 5, 14. doi:10.1186/2040-2392-5-14. https://pubmed.ncbi.nlm.nih.gov/24548729/