Table 2.
MC4R Construct | Surface Expression | Binding | Signaling cAMP
|
Functional Category | Pima Cohort | Hispanic Cohort | |
---|---|---|---|---|---|---|---|
Basal | Stimulated | ||||||
G55V | + | ↓ | ↓ | ↓ | LOF | 0 | 5a |
R165G | ↓ | ↓ | + | + | LOF | 9 | 0 |
R165Q | ↓ | ↓ | + | ↑ | LOF | 19 | 0 |
C172R | ↓ | ↓ | ↓ | ↓ | LOF | 0 | 5a |
F202L | ND | + | + | + | NFA | 0 | 3 |
M208V | + | ↓ | ↓ | ↓ | LOF | 0 | 1 |
I269N | ↓ | ↓ | + | + | LOF | 0 | 11 |
A303P | ↓ | ↓ | ↑ | + | LOF | 3 | 0 |
| |||||||
D37Stop | ↓ | LOFb | 12 | 0 | |||
V103I | + | + | + | + | GOFc | 11 | 8 |
I251L | + | + | ↑ | + | GOFc | 9 | 12 |
Abbreviations: MC4R, melanocortin-4 receptor; cAMP, 3′-5′-cyclic adenosine monophosphate; LOF, loss-of-function; NFA, non-function-altering; GOF, gain-of-function; +, no significant difference compared with common MC4R, ND, not done.
One subject was compound heterozygous for G55V and C172R.
Nine subjects heterozygous, 3 subjects homozygous for this frameshift mutation that results in premature termination prior to the ligand binding domain. Decreased stimulated cAMP generation previously reported.16 Surface expression, ligand binding, and basal activity have not been reported.
Categorized as GOF because V103I previously reported to have decreased agouti-related peptide potency, while I251L has increased basal activity.17