Human obesity has an inherited component, but in contrast to rodent obesity, precise genetic defects have yet to be defined. A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse. We have previously described a women 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. Gly-->Arg483 prevents processing of proPC1 and leads to its retention in the endoplasmic reticulum (ER). A-->C+4 of the intro-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.

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.

From March 1974 through July 1975, 76 (56%) of 133 persons who had worked at a pesticide plant that produced Kepone, a chlorinated hydrocarbon insecticide, contracted a previously unrecognized clinical illness characterized by nervousness, tremor, weight loss, opsoclonus, pleuritic and joint pain, and oligospermia. Illness incidence rates for production workers (64%) were significantly higher than for nonproduction personnel (16%). The mean blood Kepone level for workers with illness was 2.53 ppm and for those without disease 0.60 ppm (p less than 0.001). Blood Kepone levels in current workers (mean, 3.12 ppm) were higher than those in former employees (1.22 ppm). Blood Kepone levels for workers in nearby businesses and for residents of a community within 1.6 km of the plant ranged from undetectable to 32.5 ppb. Illness attributable to Kepone was found in two wives of Kepone workers; there was no apparent association between frequency of symptoms and proximity to the plant in the survey of the community population.

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 peptide products of the pro-opiomelanocortin (POMC) gene have established roles in the control of physiological processes as diverse as adrenal steroidogenesis, skin pigmentation, analgesia and inflammation. In the last 5 years, evidence accumulated from murine and human genetic models of disrupted melanocortin signalling has firmly established a central role for a population of hypothalamic neurons expressing POMC in the control of appetite and body weight. Of the five known melanocortin receptors, the MC4R has been most closely linked to body weight regulation. While a-MSH is active at this receptor and suppresses appetite after central injection, important roles for other POMC-derived products have not been excluded. The development of pharmacological agonists acting on, or mimicking, the hypothalamic melanocortinergic pathway may provide exciting opportunities for the therapy of human obesity.