Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency
Robert S. Jackson, John W.M. Creemers, I. Sadaf Farooqi, Marie-Laure Raffin-Sanson, Andrea Varro, Graham J. Dockray, Jens J. Holst, Patricia L. Brubaker, Pierre Corvol, Kenneth S. Polonsky, Diane Ostrega, Kenneth L. Becker, Xavier Bertagna, John C. Hutton, Anne White, Mehul T. Dattani, Khalid Hussain, Stephen J. Middleton, Thomasina M. Nicole, Peter J. Milla, Keith J. Lindley, Stephen O’Rahilly
Robert S. Jackson, John W.M. Creemers, I. Sadaf Farooqi, Marie-Laure Raffin-Sanson, Andrea Varro, Graham J. Dockray, Jens J. Holst, Patricia L. Brubaker, Pierre Corvol, Kenneth S. Polonsky, Diane Ostrega, Kenneth L. Becker, Xavier Bertagna, John C. Hutton, Anne White, Mehul T. Dattani, Khalid Hussain, Stephen J. Middleton, Thomasina M. Nicole, Peter J. Milla, Keith J. Lindley, Stephen O’Rahilly
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Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency

Abstract

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 glucagon-like peptide 17-36amide 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.

Authors

Robert S. Jackson, John W.M. Creemers, I. Sadaf Farooqi, Marie-Laure Raffin-Sanson, Andrea Varro, Graham J. Dockray, Jens J. Holst, Patricia L. Brubaker, Pierre Corvol, Kenneth S. Polonsky, Diane Ostrega, Kenneth L. Becker, Xavier Bertagna, John C. Hutton, Anne White, Mehul T. Dattani, Khalid Hussain, Stephen J. Middleton, Thomasina M. Nicole, Peter J. Milla, Keith J. Lindley, Stephen O’Rahilly

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Physiologically regulated, qualitatively normal POMC products were prese...
Physiologically regulated, qualitatively normal POMC products were present in Subject A’s plasma. (a) POMC is the precursor to multiple distinct peptides. N-POMC, N-terminal fragment of POMC; JP, joining peptide; αMSH, α-melanocyte stimulating hormone; βLPH, β lipotropin. (b) Concentrations of plasma cortisol (diamonds; ng/ml), ACTH (squares; pg/ml), and POMC (triangles; × 100 U/ml) were determined over 24 hours (0900 hours to 0900 hours) in Subject A. Immediately after the 0900-hours sample on day 2, a 100-μg i.v. bolus of CRH was administered. (c) HPLC of plasma sampled 20 minutes after CRH administration, with RIA of eluted C-terminal ACTH, showed peaks of phosphorylated (ACTH-p) and nonphosphorylated ACTH 1-39 (ACTH), confirming the results of direct plasma assays. Neither CLIP (a product of PC2 activity) nor immunoreactive peptides of abnormal size were present, indicating that POMC processing was of normal specificity. ↓, standards. (d) Size-exclusion gel chromatography of early-morning plasma with β endorphin RIA (triangles) and POMC IRMA (circles) of eluted peptides showed POMC and β lipotropin to be present but not β endorphin, which is a product of processing of POMC by PC2. Results are expressed as percentages of the total immunoreactivity eluted. ↓, standards.