Novel Homozygous Inactivating Mutation in the <i>PCSK1</i> Gene in an Infant with Congenital Malabsorptive Diarrhea

• Main Authors: Laetitia Aerts, Nathalie A. Terry, Nina N. Sainath, Clarivet Torres, Martín G. Martín, Bruno Ramos-Molina, John W. Creemers
• Format: Article
• Language: English
• Published: MDPI AG 2021-05-01
• Series: Genes
• Subjects: proprotein convertase 1/3; <i>PCSK1</i>; congenital malabsorptive diarrhea; endocrinopathy; enteroendocrine cells
• Online Access: https://www.mdpi.com/2073-4425/12/5/710

Proprotein convertase 1/3 (PC1/3), encoded by the <i>PCSK1</i> 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 <i>PCSK1</i> 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 <i>PCSK1</i> 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 <i>PCSK1</i> deficient patient who, despite neonatal malabsorptive diarrhea, showed a normal morphology in the small intestine.