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

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Standard

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

In: The Journal of Clinical Investigation, Vol. 112, No. 10, 11.2003, p. 1550-60.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Jackson, RS, Creemers, JWM, Farooqi, IS, Raffin-Sanson, M-L, Varro, A, Dockray, GJ, Holst, JJ, Brubaker, PL, Corvol, P, Polonsky, KS, Ostrega, D, Becker, KL, Bertagna, X, Hutton, JC, White, A, Dattani, MT, Hussain, K, Middleton, SJ, Nicole, TM, Milla, PJ, Lindley, KJ & O'Rahilly, S 2003, 'Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency', The Journal of Clinical Investigation, vol. 112, no. 10, pp. 1550-60. https://doi.org/10.1172/JCI18784

APA

Jackson, R. S., Creemers, J. W. M., Farooqi, I. S., Raffin-Sanson, M-L., Varro, A., Dockray, G. J., Holst, J. J., Brubaker, P. L., Corvol, P., Polonsky, K. S., Ostrega, D., Becker, K. L., Bertagna, X., Hutton, J. C., White, A., Dattani, M. T., Hussain, K., Middleton, S. J., Nicole, T. M., ... O'Rahilly, S. (2003). Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. The Journal of Clinical Investigation, 112(10), 1550-60. https://doi.org/10.1172/JCI18784

Vancouver

Jackson RS, Creemers JWM, Farooqi IS, Raffin-Sanson M-L, Varro A, Dockray GJ et al. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. The Journal of Clinical Investigation. 2003 Nov;112(10):1550-60. https://doi.org/10.1172/JCI18784

Author

Jackson, Robert S ; Creemers, John W M ; Farooqi, I Sadaf ; Raffin-Sanson, Marie-Laure ; Varro, Andrea ; Dockray, Graham J ; Holst, Jens Juul ; Brubaker, Patricia L ; Corvol, Pierre ; Polonsky, Kenneth S ; Ostrega, Diane ; Becker, Kenneth L ; Bertagna, Xavier ; Hutton, John C ; White, Anne ; Dattani, Mehul T ; Hussain, Khalid ; Middleton, Stephen J ; Nicole, Thomasina M ; Milla, Peter J ; Lindley, Keith J ; O'Rahilly, Stephen. / Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. In: The Journal of Clinical Investigation. 2003 ; Vol. 112, No. 10. pp. 1550-60.

Bibtex

@article{58e61f8ea8af494389ecba74651d1845,
title = "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 17-36(amide) 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.",
keywords = "Animals, Calcitonin, Endocrine System, Female, Gastrins, Glucagon, Humans, Insulin, Intestinal Absorption, Intestine, Small, Mice, Middle Aged, Pedigree, Phenotype, Pro-Opiomelanocortin, Proprotein Convertase 1, Renin",
author = "Jackson, {Robert S} and Creemers, {John W M} and Farooqi, {I Sadaf} and Marie-Laure Raffin-Sanson and Andrea Varro and Dockray, {Graham J} and Holst, {Jens Juul} and Brubaker, {Patricia L} and Pierre Corvol and Polonsky, {Kenneth S} and Diane Ostrega and Becker, {Kenneth L} and Xavier Bertagna and Hutton, {John C} and Anne White and Dattani, {Mehul T} and Khalid Hussain and Middleton, {Stephen J} and Nicole, {Thomasina M} and Milla, {Peter J} and Lindley, {Keith J} and Stephen O'Rahilly",
year = "2003",
month = nov,
doi = "10.1172/JCI18784",
language = "English",
volume = "112",
pages = "1550--60",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "10",

}

RIS

TY - JOUR

T1 - Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency

AU - Jackson, Robert S

AU - Creemers, John W M

AU - Farooqi, I Sadaf

AU - Raffin-Sanson, Marie-Laure

AU - Varro, Andrea

AU - Dockray, Graham J

AU - Holst, Jens Juul

AU - Brubaker, Patricia L

AU - Corvol, Pierre

AU - Polonsky, Kenneth S

AU - Ostrega, Diane

AU - Becker, Kenneth L

AU - Bertagna, Xavier

AU - Hutton, John C

AU - White, Anne

AU - Dattani, Mehul T

AU - Hussain, Khalid

AU - Middleton, Stephen J

AU - Nicole, Thomasina M

AU - Milla, Peter J

AU - Lindley, Keith J

AU - O'Rahilly, Stephen

PY - 2003/11

Y1 - 2003/11

N2 - 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 17-36(amide) 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.

AB - 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 17-36(amide) 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.

KW - Animals

KW - Calcitonin

KW - Endocrine System

KW - Female

KW - Gastrins

KW - Glucagon

KW - Humans

KW - Insulin

KW - Intestinal Absorption

KW - Intestine, Small

KW - Mice

KW - Middle Aged

KW - Pedigree

KW - Phenotype

KW - Pro-Opiomelanocortin

KW - Proprotein Convertase 1

KW - Renin

U2 - 10.1172/JCI18784

DO - 10.1172/JCI18784

M3 - Journal article

C2 - 14617756

VL - 112

SP - 1550

EP - 1560

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 10

ER -

ID: 132054907