Abstract
Mild periodic acid Schiff staining (mPAS) of human colonic tissue has been used to answer a variety of fundamental questions in germline and somatic genetics. mPAS stains sialic acids except when these glycans are modified by O-acetylation, but a full accounting of the genes contributing to sialoglycan acetylation is incomplete. Using haplotypes derived from whole genome sequencing, we identify a region on chromosome 11 that is associated with inherited differences in mPAS staining. Of the genes in this region, only haplotypes containing NXPE1 correlate perfectly with mPAS staining in the original cohort used for whole genome sequencing, as well as in a validation cohort. Transcriptomic analysis indicates that linked haplotypes are associated with altered expression of NXPE1 suggesting a possible genetic mechanism. Genetic manipulation of a common single nucleotide polymorphism observed in the haplotype region and located in NXPE1's promoter alters expression and causes changes to modified sialic acid levels supporting this mechanism. Finally, high-performance liquid chromatography (HPLC) confirms that enzymatically active NXPE1 is capable of transferring an acetyl group from acetyl coenzyme A to sialic acid in vitro. These findings suggest that NXPE1 is the long-sought gene responsible for differences in colon mPAS staining and may be the prototype of a new family of sialic acid O-acetylation-modifying genes.