Abstract
Proprotein convertase 1/3 (PC1/3), encoded by the PCSK1 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 PCSK1 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 PCSK1 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 PCSK1 deficient patient who, despite neonatal malabsorptive diarrhea, showed a normal morphology in the small intestine.
Highlights
The PCSK1 gene, which encodes the subtilisin-like proprotein convertase (PC) family member Proprotein convertase 1/3 (PC1/3), consists of 14 exons and is located on chromosome 5q15–21 in humans [1].The PC family consists of seven closely related members and two less-related enzymes (PCSK8 and PCSK9) [2,3]
Our results indicated that the lack of PC1/3 activity in the intestine did not result in a significative reduction of gut incretins, suggesting that deficiency of other gut hormones was responsible for the malabsorptive phenotype
PCSK1 gene, the reported in ClinVar total of 50%
Summary
The PCSK1 gene, which encodes the subtilisin-like proprotein convertase (PC) family member PC1/3, consists of 14 exons and is located on chromosome 5q15–21 in humans [1]. The PC family consists of seven closely related members (furin, PC1/3, PC2, PC4, PACE4, PC5/6, and PC7) and two less-related enzymes (PCSK8 and PCSK9) [2,3]. Despite differences in pH optima, subcellular localization, and tissue distribution of the enzymes, it has remained largely unknown which substrate is cleaved by each PC family member [4]. Some substrates can be cleaved by a specific convertase, while for other substrates, redundancy occurs. This substrate redundancy can even be tissue-specific. Roebroek et al reported that the furin knock-out mouse model displayed complete redundancy for
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
