Table 1.

Conditions caused by mutations of genes related to insulin signaling

Gene	Effect on protein function	Effect on insulin action	Frequency	Condition caused	Other characteristics
INSR	Loss	Resistance	Relatively common (> 200)	Type A insulin resistance, Donohue, and Rabson–Mendenhall syndromes	Acanthosis nigricans, polycystic ovary, hirsutism (in type A insulin resistance); early death (in Donohue and Rabson–Mendenhall)
PIK3R1	Loss	Resistance	Rare (> 30)	SHORT syndrome	Short stature, facial characteristics
PIK3R2	Gain	Sensitivity	Rare (> 10)	None	Segmental overgrowth or megalencephaly
PIK3CA	Gain	Sensitivity	Rare (> 60)	None	Segmental overgrowth or megalencephaly
AKT1	Gain	Not known	Rare (> 20)	Proteus syndrome	Overgrowth of various tissues, mosaic mutation
AKT2	Loss	Resistance	Very rare (3)	None	Hypertension
	Gain	Sensitivity	Very rare (1)	None	Overgrowth, hypoglycemia
AKT3	Gain	Not known	Very rare (~ 3)	None	Megalencephaly
TBC1D4	Loss	Resistance	Very rare (1)	None	Acanthosis nigricans, postprandial hyperinsulinemia
PTEN	Loss	Sensitivity	Relatively common (> 300)a	Cowden syndrome	Hamartoma, cancer predisposition
PTPN11	Gain	Resistance	Relatively common (> 800)b	Noonan syndrome	Short stature, congenital heart disease, skeletal malformation
PRKCE	Loss	Nonec	Very rare (1)	SHORT syndrome	Short stature, facial characteristics

Numbers in parentheses for frequency indicate the number of cases or families described in published reports

^aFifteen families have been evaluated for glucose tolerance or insulin sensitivity

^bOne family has been evaluated for glucose tolerance or insulin sensitivity

^cThe patient might have been too young to develop apparent insulin resistance