Heterozygous mutations in INSR [OMIM#147670] have been described in patients with type A insulin resistance [OMIM#610549], which is a type of extreme insulin resistance characterized by hyperinsulinemia and acanthosis nigricans, in addition to signs of hyperandrogenism in normal weight females without lipodystrophy. Homozygous or compound heterozygous mutations in INSR have been associated with Donohue syndrome [OMIM#246200] and Rabson-Medenhall syndrome [OMIM#262190], which are severe insulin resistance disorders characterized by intrauterine and postnatal growth retardation, facial dysmorphism, lack of subcutaneous fat, hyperinsulinemia, acanthosis nigricans and reduced life expectancy.
INSR encodes for the insulin receptor, and mutations in this gene lead to resistance to the physiological effects of insulin, and consequent compensatory increased insulin secretion. It is thought that phenotypic severity is determined by the degree of insulin binding capacity that remains. Heterozygous mutations are hypothesized to have a dominant negative effect and interfere with the function of the normal allele. Patients with the most severe INSR-related disorder, Donohue syndrome, have severely reduced insulin binding, whereas those with the less severe Rabson-Mendenhall syndrome retain some insulin binding capacity.