Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene

Abstract

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.

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…101,104,114,154,155 Early onset of morbid obesity associated with CHH suggests mutations in LEP, LEPR or PCSK1. 58,156 Indeed, combining CHH with specific associated phenotypes can increase the probability of finding causal mutations by targeted gene sequencing ( Figure 4). 21,28,104,157 CHH accompanied by other syndromic features such as congenital ichthyosis 158 or spherocytosis 159 is suggestive of a contiguous gene syndrome for which a karyotype or comparative genomic hybridization array analysis might be useful for identifying underlying chromosomal abnormalities.…”

Chronic stress aggravates glucose intolerance in leptin receptor-deficient (db/db) mice

“…The db/db mouse is analogous to human homozygotes for a mutation corresponding to a truncated form of the leptin receptor; these patients present early onset obesity associated with hyperleptinemia, impulsive eating behavior and emotional liability (Clément et al 1998). Similarly, other monogenic forms of human obesity have been associated with mutations of genes involved in the melanocortin signaling pathway such as: proopiomelanocortin (Krude et al 1998), prohormone convertase 1 (Jackson et al 1997) and melanocortin 4 receptor . All these forms of non-syndromic monogenic obesity share an early onset obesity that is largely dependent on excessive caloric consumption, suggesting a potential therapeutic approach based on the control the food intake (Meyre and Froguel 2010).…”

Controle neuroendócrino do peso corporal: implicações na gênese da obesidade

“…Os níveis de POMC também estavam muito elevados, sugerindo um defeito generalizado na conversão de pró-hormônios. Foram detectadas 2 mutações (heterozigose composta) com perda de função da PC1 (71). A intolerância à glicose e a hipoglicemia pós-prandial resultaram da menor atividade biológica e da maior meia-vida da pró-insulina em relação à insulina, respectivamente.…”