Robert S. Jackson

Publications (3)57.57 Total impact

• Article: 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, [......], 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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  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.
  Journal of Clinical Investigation 12/2003; 112(10):1550-60. · 15.39 Impact Factor
• Article: Molecular and cellular regulation of prohormone processing

  John W.M. Creemers, Robert S. Jackson, John C. Hutton
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  ABSTRACT: The processing of prohormones involves cleavage at specific basic amino acids by members of the subtilisin-like serine endoprotease family, followed by trimming of the COOH terminus by carboxypeptidase E. The enzymes are regulated by the intra-organelle ionic environment, through post-translational processing and by interaction with endogenous inhibitors. Much has been learned about their catalytic function and cell biology from in vitro gene transfer experiments using chimeric molecules and by site-directed mutagenesis. Further insight into their molecular properties and physiological function has been gained recently from the study of in vivo mutants.
  Seminars in Cell and Developmental Biology 02/1998; 9(1):3-9. · 6.65 Impact Factor
• Article: Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene

  Robert S. Jackson, John W.M. Creemers, Shinya Ohagi, Marie-Laure Raffin-Sanson, Louise Sanders, Carl T. Montague, John C. Hutton, Stephen O'Rahilly
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  ABSTRACT: Human obesity has an inherited component, but in contrast to rodent obesity, precise genetic defects have yet to be defined1. A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse2,3. We have previously described a woman with extreme childhood obesity (Fig. 1), abnormal glucose homeostasis, hypogonadotrophic hypogonadism, hypocortisolism and elevated plasma proinsulin and pro-opiomelanocortin (POMC) concentrations but a very low insulin level, suggestive of a defective prohormone processing by the endopeptidase, prohormone convertase 1 (PC1; ref. 4). We now report this proband to be a compound heterozygote for mutations in PC1. GlyArg483 prevents processing of proPd and leads to its retention in the endoplasmic reticulum (ER). AC+4 of the intron-5 donor splice site causes skipping of exon 5 leading to loss of 26 residues, a frameshift and creation of a premature stop codon within the catalytic domain. PC1 acts proximally to CPE in the pathway of post-translational processing of prohormones and neuropeptides. In view of the similarity between the proband and the fat/fat mouse phenotype, we infer that molecular defects in prohormone conversion may represent a generic mechanism for obesity, common to humans and rodents.
  Nature Genetics 06/1997; 16(3):303-306. · 35.53 Impact Factor