Genetic mutations resulting in loss of aromatase activity in humans and mice

Abstract

Aromatase enzyme is the product of the CYP19 gene. Human aromatase deficiency is a rare disorder and is usually caused by single base-pair changes resulting in amino acid substitution or premature stop codons. In most cases, the affected mother presents with virilization in the third trimester of pregnancy. Affected female newborns have pseudohemaphrodism with clitoromegaly and hypospadias. The cause of these presentations in pregnancy is the inability to convert fetal dehydroepiandrosterone to estrogen in the placenta and subsequent conversion to androgens in the periphery. Affected male newborns present with tall stature secondary to failed epiphyseal fusion. They also have delayed bone age, osteopenia, and undermineralization, which can be corrected with the addition of estrogen, highlighting estrogen's critical role in men as well as women. The aromatase knock-out male mouse (ArKO) has shortened femur length and bone undermineralization. Female ArKO mice at 10-12 weeks have multiple ovarian follicles arrested in the antral phase and stromal hyperplasia. By 1 year the ovaries become grossly dysmorphic with numerous cystic follicles and fibrous stroma. Male ArKO mice testes demonstrate arrest of spermatogenesis at the level of round spermatids and Leydig cell hyperplasia. ArKO mice also exhibit evidence of insulin resistance and visceral adiposity.