Alterations in the expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure

Abstract

Premature ovarian failure (POF) is characterized by hypergonadotropic hypogonadism and amenorrhea before the age of 40. The condition has a heterogeneous background but genetic factors are demonstrated by the occurrence of familial cases. We identified a mother and daughter with POF both of whom carry an X;autosome translocation [t(X;11)(q24;q13)]. RNA expression studies of genes flanking the X-chromosome breakpoint revealed that both patients have reduced expression levels of the gene Progesterone Receptor Membrane Component-1 (PGRMC1). Mutation screening of 67 females with idiopathic POF identified a third patient with a missense mutation (H165R) located in the cytochrome b5 domain of PGRMC1. PGRMC1 mediates the anti-apoptotic action of progesterone in ovarian cells and it acts as a positive regulator of several cytochrome P450 (CYP)-catalyzed reactions. The CYPs are critical for intracellular sterol metabolism, including biosynthesis of steroid hormones. We show that the H165R mutation associated with POF abolishes the binding of cytochrome P450 7A1 (CYP7A1) to PGRMC1. In addition, the missense mutation attenuates PGRMC1's ability to mediate the anti-apoptotic action of progesterone in ovarian cells. These findings suggest that mutant or reduced levels of PGMRC1 may cause POF through impaired activation of the microsomal cytochrome P450 and increased apoptosis of ovarian cells.

Progesterone receptor membrane component 1 expression and putative function in bovine oocyte maturation, fertilization, and early embryonic development

“…[t(X;11)(q24;q13)]). This X chromosome translocation likely depletes one copy of PGRMC1, thereby accounting for the reduced level of PGRMC1 in these women (Mansouri et al 2008). The second condition involves a single base mutation in which the histidine at residue 165 is changed to arginine.…”

Genetics of primary ovarian insufficiency

“…Further, a missense substitution located in the intracellular C-terminus of PGRMC1, which impair the anti-apoptotic action of progesterone in the developing ovary leading to premature ovarian follicles depletion, has been found at the heterozygous state by the genetic screening of 67 women with POI (155).…”

PGRMC1 participates in late events of bovine granulosa cells mitosis and oocyte meiosis

“…[3][4][5] Its clinical relevance is indicated by studies showing that altered PGRMC1 expression correlates with defective follicular development and infertility in women. [6][7][8] Primary evidence that PGRMC1 has a fundamental role in ovarian somatic cells comes from in vivo studies in mice, in which conditional knockout of PGRMC1 in granulosa cells impairs antral follicle development. 2,9 Accordingly, in vitro studies using different ovarian cell lines have shown that depleting PGRMC1 expression suppresses cell proliferation.…”