TY - JOUR

T1 - Mutational Landscape of the Proglucagon-Derived Peptides

AU - Lindquist, Peter

AU - Madsen, Jakob S.

AU - Brauner-Osborne, Hans

AU - Rosenkilde, Mette M.

AU - Hauser, Alexander S.

PY - 2021

Y1 - 2021

N2 - Strong efforts have been placed on understanding the physiological roles and therapeutic potential of the proglucagon peptide hormones including glucagon, GLP-1 and GLP-2. However, little is known about the extent and magnitude of variability in the amino acid composition of the proglucagon precursor and its mature peptides. Here, we identified 184 unique missense variants in the human proglucagon gene GCG obtained from exome and whole-genome sequencing of more than 450,000 individuals across diverse sub-populations. This provides an unprecedented source of population-wide genetic variation data on missense mutations and insights into the evolutionary constraint spectrum of proglucagon-derived peptides. We show that the stereotypical peptides glucagon, GLP-1 and GLP-2 display fewer evolutionary alterations and are more likely to be functionally affected by genetic variation compared to the rest of the gene products. Elucidating the spectrum of genetic variations and estimating the impact of how a peptide variant may influence human physiology and pathophysiology through changes in ligand binding and/or receptor signalling, are vital and serve as the first important step in understanding variability in glucose homeostasis, amino acid metabolism, intestinal epithelial growth, bone strength, appetite regulation, and other key physiological parameters controlled by these hormones.

AB - Strong efforts have been placed on understanding the physiological roles and therapeutic potential of the proglucagon peptide hormones including glucagon, GLP-1 and GLP-2. However, little is known about the extent and magnitude of variability in the amino acid composition of the proglucagon precursor and its mature peptides. Here, we identified 184 unique missense variants in the human proglucagon gene GCG obtained from exome and whole-genome sequencing of more than 450,000 individuals across diverse sub-populations. This provides an unprecedented source of population-wide genetic variation data on missense mutations and insights into the evolutionary constraint spectrum of proglucagon-derived peptides. We show that the stereotypical peptides glucagon, GLP-1 and GLP-2 display fewer evolutionary alterations and are more likely to be functionally affected by genetic variation compared to the rest of the gene products. Elucidating the spectrum of genetic variations and estimating the impact of how a peptide variant may influence human physiology and pathophysiology through changes in ligand binding and/or receptor signalling, are vital and serve as the first important step in understanding variability in glucose homeostasis, amino acid metabolism, intestinal epithelial growth, bone strength, appetite regulation, and other key physiological parameters controlled by these hormones.

KW - proglucagon

KW - pharmacogenomics

KW - GLP-1

KW - GLP-2

KW - glucagon

KW - GPCR

KW - mutant

KW - GCG

KW - GLUCAGON-LIKE PEPTIDE-1

KW - PROTEIN-COUPLED RECEPTORS

KW - INSULIN-SECRETION

KW - EVOLUTION

KW - BINDING

KW - PHYSIOLOGY

KW - TYPE-2

KW - IDENTIFICATION

KW - CONSEQUENCES

U2 - 10.3389/fendo.2021.698511

DO - 10.3389/fendo.2021.698511

M3 - Journal article

C2 - 34220721

VL - 12

JO - Frontiers in Endocrinology

JF - Frontiers in Endocrinology

SN - 1664-2392

M1 - 698511

ER -