PCSK1 Variants and Human Obesity

摘要: PCSK1, encoding prohormone convertase 1/3 (PC1/3), was one of the first genes linked to monogenic early-onset obesity. PC1/3 is a protease involved in biosynthetic processing variety neuropeptides and prohormones endocrine tissues. activity essential for activating cleavage many peptide hormone precursors implicated regulation food ingestion, glucose homeostasis, energy example, proopiomelanocortin, proinsulin, proglucagon, proghrelin. A large number genome-wide association studies different populations have now firmly established link between three PCSK1 polymorphisms frequent population increased risk Human subjects with deficiency, rare autosomal-recessive disorder caused by presence loss-of-function mutations both alleles, are obese display complex set endocrinopathies. Increasing numbers genetic diagnoses infants persistent diarrhea has recently led finding novel mutations. PCSK1-deficient experience severe intestinal malabsorption during years life, requiring controlled nutrition; these children then become hyperphagic, associated The biochemical characterization resulted discovery new pathological mechanisms affecting cell biology beyond simple loss enzyme activity, dominant-negative effects certain mutants on wild-type protein, activation cellular unfolded protein response endoplasmic reticulum-retained mutants. better understanding molecular pathologies may illuminate possible treatments endocrinopathy including