NXPE1 alters the sialoglycome by acetylating sialic acids in the human colon

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 staining is known to reflect sialic acid O-acetylation, but a full accounting of the genes contributing to sialoglycome diversity is incomplete. Using haplotypes derived from whole genome sequencing, we identified a region on chromosome 11 that is associated with inherited differences in mPAS staining. Of the genes in this region, only NXPE1 haplotypes correlated perfectly with mPAS staining in the original cohort used for whole genome sequencing, as well as in a validation cohort. Transcriptomic analysis suggested that one common allele of NXPE1, with a single base pair substitution in its promoter region, greatly reduces expression of the gene. Genetic manipulation of NXPE1 expression confirmed this conclusion and caused changes to modified sialic acid levels. 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.