Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency

Abstract

The biosynthesis of many secreted peptides involves limited endoproteolysis of larger, usually inactive, precursors to release the bioactive fragments. A family of serine endoproteases (proprotein convertases) that perform this processing function within the secretory pathway has been defined (1-3). Two members, proprotein convertases 1 and 2 (PC1 and PC2), which show expression confined to the regulated secretory pathway of neuroendocrine tissue, have been particularly closely studied. Although ex vivo experiments indicate that their substrate specificities overlap, in vivo they appear We have previously described the only reported case of human proprotein convertase 1 (PC1) deficiency, in a female (Subject A) with obesity, hypogonadism, hypoadrenalism, and reactive hypoglycemia. We now report the second case of human PC1 deficiency (Subject B), also due to compound heterozygosity for novel missense and nonsense mutations. While both subjects shared the phenotypes of obesity, hypoadrenalism, reactive hypoglycemia, and elevated circulating levels of certain prohormones, the clinical presentation of Subject B was dominated by severe refractory neonatal diarrhea, malabsorptive in type. Subsequent investigation of Subject A revealed marked small-intestinal absorptive dysfunction, which was not previously clinically suspected. We postulate that PC1, presumably in the enteroendocrine cells, is essential for the normal absorptive function of the human small intestine. The differences in the nature and severity of presentation between the two cases cannot readily be explained on the basis of allelic heterogeneity, as the nonsense and missense mutations from both subjects had comparably severe effects on the catalytic activity of PC1. Despite Subject A's negligible PC1 activity, some mature ACTH and glucagonlike peptide 1 7-36amide were detectable in her plasma, suggesting that the production of these hormones, at least in humans, does not have an absolute dependence on PC1. The presence of severe obesity and the absence of growth retardation in both subjects contrast markedly with the phenotype of mice lacking PC1 and suggest that the precise physiological repertoire of this enzyme may vary between mammalian species.

The role of gut hormones in glucose homeostasis

“…An inactivating mutation in the gene encoding PC1 has been described in several subjects (122). Although loss of PC1 action might be predicted to include relative deficiency of bioactive GIP and GLP1, the glucose intolerance, intractable diarrhea, and malabsorption phenotype in these individuals probably obscures the potential importance of loss of incretin action in this setting.…”

The regulation of appetite

“…14 Obesity can also result when, despite normal POMC transcription and translation, there is a problem with peptide processing, such as congenital deficiency of the processing enzyme prohormone convertase 1. 15 16 The receptors for the POMC cleavage product play a role in energy balance. The MC4 receptor is implicated in as much as 6% of severe early onset human obesity, 17 while a particular variant of the receptor is negatively associated with obesity.…”

Molecular Genetic Analysis of Normosmic Hypogonadotropic Hypogonadism in a Turkish Population: Identification and Detailed Functional Characterization of a Novel Mutation in the Gonadotropin-Releasing Hormone Receptor Gene

“…Additionally, it has recently been shown that loss-of-function mutations of the G protein-coupled receptor, GPR54 , lead to nIHH in a few cases [7]. The other clinical entities associated with nIHH include leptin and leptin receptor defects [8], which are both characterized by severe childhood-onset obesity and hyperphagia, and prohormone convertase defects which present with childhood-onset obesity, hypoinsulinemia, and hypocortisolemia [9]. …”