Pcsk1, encoding prohormone convertase 1/3 (PC1/3), is a gene of great significance. PC1/3 is a protease involved in the biosynthetic processing of various neuropeptides and prohormones in endocrine tissues. It is essential for the activating cleavage of many peptide hormone precursors associated with the regulation of food ingestion, glucose homeostasis, and energy homeostasis, such as proopiomelanocortin, proinsulin, proglucagon, and proghrelin [1,2].

A large number of genome-wide association studies have linked three PCSK1 polymorphisms to an increased risk of obesity [1]. Human subjects with PC1/3 deficiency, caused by loss-of-function mutations in both alleles, are obese and display a complex set of endocrinopathies [1,2]. Additionally, PCSK1-deficient infants experience severe intestinal malabsorption in early life, followed by hyperphagia and obesity [1]. Biochemical characterization of novel loss-of-function PCSK1 mutations has revealed new pathological mechanisms beyond simple loss of enzyme activity, like dominant-negative effects on wild-type PC1/3 protein and activation of the cellular unfolded protein response [1].

In conclusion, Pcsk1 plays a crucial role in the processing of neuropeptides and prohormones related to energy and glucose homeostasis. Studies on human subjects with Pcsk1 deficiency have provided insights into its role in obesity and associated endocrinopathies. Understanding the molecular and cellular pathologies related to Pcsk1 may offer potential treatments for these complex conditions [1].