Table 2.

Summary of Functional Properties of Variant MC4Rs and Their Distribution in the Cohorts Studied

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.

^aOne subject was compound heterozygous for G55V and C172R.

^bNine 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.

^cCategorized as GOF because V103I previously reported to have decreased agouti-related peptide potency, while I251L has increased basal activity.¹⁷