Abstract
The proprotein convertase subtilisin/Kexin type 1 (PCSK1/PC1) protein processes inactive pro-hormone precursors into biologically active hormones in a number of neuroendocrine and endocrine cell types. Patients with recessive mutations in PCSK1 exhibit a complex spectrum of traits including obesity, diarrhoea and endocrine disorders. We describe here a new mouse model with a point mutation in the Pcsk1 gene that exhibits obesity, hyperphagia, transient diarrhoea and hyperproinsulinaemia, phenotypes consistent with human patient traits. The mutation results in a pV96L amino acid substitution and changes the first nucleotide of mouse exon 3 leading to skipping of that exon and in homozygotes very little full-length transcript. Overexpression of the exon 3 deleted protein or the 96L protein results in ER retention in Neuro2a cells. This is the second Pcsk1 mouse model to display obesity phenotypes, contrasting knockout mouse alleles. This model will be useful in investigating the basis of endocrine disease resulting from prohormone processing defects.
Highlights
Proprotein convertases (PCs) proteolytically processes inactive pro-hormone precursors into biologically active peptides (Turpeinen et al 2013)
Proprotein convertase subtilisin/Kexin types 1 and 2 (PCSK1 and PCSK2) are found in neuroendocrine and endocrine cells cleaving a range of targets including proinsulin (Furuta et al 1998; Smeekens et al 1992; Zhu et al 2002a), progonadotrophin-releasing hormone (GnRH) (Wetsel et al 1995), proopiomelanocortin (POMC)(Benjannet et al 1991; Zhou et al 1993), proglucagon (Dhanvantari et al 1996; Rouille et al 1995), prothyrotrophin-releasing hormone (Schaner et al 1997), pro-growth hormone-releasing hormone (Dey et al 2004; Posner et al 2004), proghrelin (Zhu et al 2006) and prosomatostatin (Galanopoulou et al 1993)
A mouse pedigree designated MUTA-PED-C3PDE-242 (MPC-242) exhibiting early onset obesity and hyperinsulinemia was observed in a N-ethyl-N-nitrosourea (ENU) mutagenesis screen for age related disease (Potter et al 2016)
Summary
Proprotein convertases (PCs) proteolytically processes inactive pro-hormone precursors into biologically active peptides (Turpeinen et al 2013). At least 26 cases of congenital recessive PCSK1 deficiency have been reported, and consistent with their function exhibited a variable range of symptoms that include malabsorptive diarrhoea, obesity and various endocrine disorders (reviewed Pepin et al 2019; Stijnen et al 2016). These latter including hyperproinsulinaemia, hypogonadism, hypercortisolism, postprandial hypoglycaemia, hypothyroidism and growth hormone (GH) deficiency (Pepin et al 2019; Stijnen et al 2016). It has been reported that deficiency of PCSK1 impairs prohormone processing in Prader-Willi syndrome (Burnett et al 2017)
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