RGD Reference Report - Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. - Rat Genome Database

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

Authors: Jackson, RS  Creemers, JW  Ohagi, S  Raffin-Sanson, ML  Sanders, L  Montague, CT  Hutton, JC  O'Rahilly, S 
Citation: Jackson RS, etal., Nat Genet. 1997 Jul;16(3):303-6.
RGD ID: 1601274
Pubmed: PMID:9207799   (View Abstract at PubMed)
DOI: DOI:10.1038/ng0797-303   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
obesity  IAGP 1601274 RGD 
obesity  ISOPCSK1 (Homo sapiens)1601274; 1601274DNA:missense mutation:cds: p.G483R (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Obesity  IAGP 1601274DNA:missense mutation:cds: p.G483R (human)RGD 
Objects Annotated

Genes (Rattus norvegicus)
Pcsk1  (proprotein convertase subtilisin/kexin type 1)

Genes (Mus musculus)
Pcsk1  (proprotein convertase subtilisin/kexin type 1)

Genes (Homo sapiens)
PCSK1  (proprotein convertase subtilisin/kexin type 1)


Additional Information