title: 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.
authors.affiliation: Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Mahmoud Reza
authors.initials: MR
authors.lastname: Mansouri
authors.forename: Jens
authors.initials: J
authors.lastname: Schuster
authors.forename: Jitendra
authors.initials: J
authors.lastname: Badhai
authors.forename: Eva-Lena
authors.initials: EL
authors.lastname: Stattin
authors.forename: Ralf
authors.initials: R
authors.lastname: Lösel
authors.forename: Martin
authors.initials: M
authors.lastname: Wehling
authors.forename: Birgit
authors.initials: B
authors.lastname: Carlsson
authors.forename: Outi
authors.initials: O
authors.lastname: Hovatta
authors.forename: Per Olof
authors.initials: PO
authors.lastname: Karlström
authors.forename: Irina
authors.initials: I
authors.lastname: Golovleva
authors.forename: Daniela
authors.initials: D
authors.lastname: Toniolo
authors.forename: Silvia
authors.initials: S
authors.lastname: Bione
authors.forename: John
authors.initials: J
authors.lastname: Peluso
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D041321:Chromosomes, Human, X / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D016649:Primary Ovarian Insufficiency / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017434:Protein Structure, Tertiary; D011980:Receptors, Progesterone / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C115296:PGRMC1 protein, human; D011980:Receptors, Progesterone; D003577:Cytochrome P-450 Enzyme System
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