Table 3.
Identified MC4R variants among 1261 Danish children and adolescents with overweight or obesity.
| Type of mutation | AA change | Nucleotide change | SNP ID | Carriers (n) | In vitro functional analyses | |
|---|---|---|---|---|---|---|
| Functional effect | References | |||||
| Classified as “damaging” (total number of carriers with damaging mutation: n = 25) | ||||||
| Nonsense | p.Y35X and p.D37V |
c.105C>A ac.110A>T |
rs13447324 rs13447325 |
12a | Reduced ligand-induced cAMP signaling, reduced cell-surface expression | [28, 29, 32, 35] |
| Missense | p.R165Q | c.494G>A | NA | 8 | Reduced ligand-induced cAMP and ERK1/2 signaling | [8, 29, 30, 32, 33, 35, 55] |
| Loss of function | [34] | |||||
| Missense | p.G181D | c.542G>A | rs13447333 | 1 | Loss of function, reduced cell-surface expression | [14, 28, 31, 35] |
| Missense | p.A219V | c.656C>T | rs121913567 | 4 | Reduced ligand-induced cAMP signaling, reduced basal pERK1/2 levels | [31, 55–57] |
| Classified as “unresolved” (total number of carriers with unresolved mutation: n = 6) | ||||||
| Missense | p.T112M | c.335C>T | rs13447329 | 2 | Cell-surface expression, ligand binding, and cAMP accumulation as WT | [14, 28, 37–39, 41] |
| Reduced cell-surface expression, impaired ligand-stimulated ERK1/2 activation | [34, 55] | |||||
| Reduced potency for some endogenous ligands | [29] | |||||
| Missense | p.I170V | c.508A>G | rs121913560 | 3a | Ligand-induced cAMP and ERK1/2 signaling as WT | [29, 42, 55, 58] |
| Reduced ligand-induced cAMP signaling, reduced cell-surface expression | [13, 34, 40, 58] | |||||
| Missense | p.V253I | c.757G>A | rs187152753 | 1 | As WT | [29, 34, 40] |
| Reduced ligand-induced cAMP signaling | [33] | |||||
| Classified as “benign” (total number of carriers with benign mutation: n = 71) | ||||||
| Missense | p.S30F | c.89C>T | rs13447323 | 1 | As WT, agonist-stimulated ERK1/2 activation | [4, 28, 30, 38, 40, 43, 55] |
| Missense | p.M200V | c.598A>G | NA | 2 | Cell-surface expression, ligand-induced cAMP and ERK1/2 signaling as WT | [14, 36, 37, 55] |
| Missense | p.P275S | c.823C>T | rs201813179 | 1 | As WT | [32] |
| Missense | p.V103I | c.307G>A | rs2229616 | 38 | As WT | [13, 14, 28, 32, 39] |
| Gain of function | [29] | |||||
| Missense | p.I251L | c.751A>C | rs52820871 | 29 | As WT | [13, 14, 28, 32] |
| Gain of function | [29] | |||||
Identified MC4R variants, their overall classification in this study and their corresponding change in amino acid composition and nucleotides. For each identified variant, SNP ID and number of carriers are listed. Functional effects, as examined by in vitro analyses, are summarized and cited with references; based on this, the overall classification of each variant is provided.
AA amino acid, ERK1/2 extracellular signal-regulated kinases 1 and 2, SNP single nucleotide polymorphism.
aOne child carried both the p.Y35X and p.D37V/ac.110A>T haplotype and the p.I170V variant.