Mutational Landscape of the Proglucagon-Derived Peptides
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Mutational Landscape of the Proglucagon-Derived Peptides. / Lindquist, Peter; Madsen, Jakob S.; Brauner-Osborne, Hans; Rosenkilde, Mette M.; Hauser, Alexander S.
I: Frontiers in Endocrinology, Bind 12, 698511, 2021.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 -
ID: 274067059