Centre of Human Genetics, Laboratory for Biochemical Neuroendocrinology, 3000 KU Leuven, Belgium.
Department of Pediatrics, Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Genes (Basel). 2021 May 10;12(5):710. doi: 10.3390/genes12050710.
Proprotein convertase 1/3 (PC1/3), encoded by the gene, is expressed in neuronal and (entero)endocrine cell types, where it cleaves and hence activates a number of protein precursors that play a key role in energy homeostasis. Loss-of-function mutations in cause a recessive complex endocrinopathy characterized by malabsorptive diarrhea and early-onset obesity. Despite the fact that neonatal malabsorptive diarrhea is observed in all patients, it has remained understudied. The aim of this study was to investigate the enteroendocrine pathologies in a male patient with congenital deficiency carrying the novel homozygous c.1034A>C (p.E345A) mutation. This patient developed malabsorptive diarrhea and metabolic acidosis within the first week of life, but rapid weight gain was observed after total parenteral nutrition, and he displayed high proinsulin levels and low adrenocorticotropin. In vitro analysis showed that the p.E345A mutation in PC1/3 resulted in a (near) normal autocatalytic proPC1/3 processing and only partially impaired PC1/3 secretion, but the processing of a substrate in trans was completely blocked. Immunohistochemical staining did not reveal changes in the proGIP/GIP and proglucagon/GLP-1 ratio in colonic tissue. Hence, we report a novel deficient patient who, despite neonatal malabsorptive diarrhea, showed a normal morphology in the small intestine.
脯氨酸羧肽酶 1/3（PC1/3）由 基因编码，在神经元和（肠）内分泌细胞类型中表达，在这些细胞中它可切割并激活许多在能量平衡中起关键作用的蛋白前体。 基因的功能丧失突变导致隐性复杂内分泌病，其特征为吸收不良性腹泻和早发性肥胖。尽管所有患者均观察到新生儿吸收不良性腹泻，但对其研究仍不足。本研究旨在研究携带新型纯合 c.1034A>C（p.E345A）突变的先天性 缺陷男性患者的肠内分泌病理学。该患者在出生后的第一周内出现吸收不良性腹泻和代谢性酸中毒，但在全胃肠外营养后体重迅速增加，且表现为高胰岛素原水平和促肾上腺皮质激素水平低。体外分析表明，PC1/3 中的 p.E345A 突变导致（几乎）正常的自身催化 proPC1/3 加工，仅部分损害 PC1/3 分泌，但转译加工完全受阻。免疫组织化学染色未显示结肠组织中 proGIP/GIP 和 proglucagon/GLP-1 比例发生变化。因此，我们报告了一例新型 缺陷患者，尽管有新生儿吸收不良性腹泻，但小肠形态正常。
