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

Mahmoud Reza Mansouri, Jens Schuster, Jitendra Badhai, Eva Lena Stattin, Ralf Lösel, Martin Wehling, Birgit Carlsson, Outi Hovatta, Per Olof Karlström, Irina Golovleva, Daniela Toniolo, Silvia Bione, John Peluso, Niklas Dahl

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3776-3783
Number of pages8
JournalHuman Molecular Genetics
Volume17
Issue number23
DOIs
Publication statusPublished - 2008

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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