Lee Bum Seok, Cook Ashley, Sur Surojit, Dobbyn Laura, Popoli Maria, Khalili Sana, Zhou Shibin, Bettegowda Chetan, Papadopoulos Nickolas, Gabrielson Kathy, Buckhaults Phillip, Vogelstein Bert, Kinzler Kenneth W, Wyhs Nicolas
Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nat Commun. 2025 May 27;16(1):4912. doi: 10.1038/s41467-025-59671-9.
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.
人结肠组织的轻度过碘酸希夫染色（mPAS）已被用于解答生殖系和体细胞遗传学中的各种基本问题。mPAS可对唾液酸进行染色，除非这些聚糖被O-乙酰化修饰，但对促成唾液酸糖乙酰化的基因的全面了解仍不完整。利用全基因组测序得到的单倍型，我们在11号染色体上确定了一个与mPAS染色的遗传差异相关的区域。在该区域的基因中，只有包含NXPE1的单倍型与用于全基因组测序的原始队列以及验证队列中的mPAS染色完美相关。转录组分析表明，连锁单倍型与NXPE1表达改变相关，提示可能存在遗传机制。在单倍型区域观察到的、位于NXPE1启动子中的常见单核苷酸多态性的基因操作改变了表达，并导致修饰唾液酸水平发生变化，支持了这一机制。最后，高效液相色谱（HPLC）证实，具有酶活性的NXPE1能够在体外将乙酰辅酶A的乙酰基转移到唾液酸上。这些发现表明，NXPE1是长期以来寻找的负责结肠mPAS染色差异的基因，可能是唾液酸O-乙酰化修饰基因新家族的原型。
