PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders

Abstract

Prohormone convertase 1/3, encoded by the PCSK1 gene, is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones. Humans who are homozygous or compound heterozygous for loss-of-function mutations in PCSK1 exhibit a variable and pleiotropic syndrome consisting of some or all of the following: obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels in association with elevated circulating proinsulin-to-insulin ratio. Recently, more common variants in the PCSK1 gene have been found to be associated with alterations in body mass index, increased circulating proinsulin levels, and defects in glucose homeostasis. This review provides an overview of the endocrinopathies and other disorders observed in prohormone convertase 1/3-deficient patients, discusses the possible biochemical basis for these manifestations of the disease, and proposes a model whereby certain missense mutations in PCSK1 may result in proteins with a dominant negative action.

POMC: The Physiological Power of Hormone Processing

“…Surprisingly, even though there was an absence of ACTH, there was no difference in corticosterone (449), suggesting that perhaps the higher levels of POMC could compensate for the lack of ACTH. However, this has not been confirmed by other studies (387). Relative levels of other POMC-derived peptides were not altered in PC1/3 null mice (291), indicating some adaptation or compensation.…”

“…All pro-hormone convertases are themselves derived from precursors and are trafficked to the secretory granules where POMC processing occurs. The maturation of PC1/3 from its precursor is described by Stijnen et al (387). PC1/3 has a signal peptide and an 80 -90 amino acid prosegment at the NH 2 terminal.…”

Proprotein convertase furin regulates osteocalcin and bone endocrine function

“…In particular, the PCs of the subtilisin/kexin type include proprotein convertase 1 (PC1), proprotein convertase 2 (PC2), furin, proprotein convertase 4 (PC4), proprotein convertase 5A and B (PC5A and PC5B), paired basic aa-cleaving enzyme 4 (PACE4), and proprotein convertase 7 (PC7) and play critical functions in several endocrine cells by regulating the maturation and secretion of numerous peptide hormones such as insulin, glucagon, adrenocorticotropic hormone (ACTH), glucagon-like peptide 1 (GLP-1), and parathyroid hormone (PTH) (18,19).…”

Furin controls β cell function via mTORC1 signaling

“…For instance, PC1/3 and PC2 are both highly expressed in the secretory granules of neuronal and endocrine cells and process a number of hormones and neuropeptides involved in the regulation of glucose and energy homeostasis such as insulin, glucagon and proopiomelanocortin (POMC) (1,2). In humans, rare homozygous and compound heterozygous mutations that cause complete loss of PC1/3 enzymatic activity lead to hyperphagic obesity and impaired glucose homeostasis, among other endocrinopathies (5). In addition, common heterozygous PC1/3 mutations that cause partial loss-of-function contribute to variation in human body mass index (BMI) and plasma proinsulin and are associated with impaired regulation of plasma glucose levels (6).…”