Human Molecular Genetics Advance Access originally published online on September 9, 2008
Human Molecular Genetics 2008 17(23):3776-3783; doi:10.1093/hmg/ddn274
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Published by Oxford University Press 2008
Alterations in the expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure
1 Department of Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden 2 Medical and Clinical Genetics, Department of Medical Biosciences, Umeå University, 901 85 Umeå, Sweden 3 Clinical Pharmacology Mannheim, University of Heidelberg, 68135 Mannheim, Germany 4 Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 86 Stockholm, Sweden 5 Department of Women’s and Children’s Health, Academic Hospital, 751 85 Uppsala, Sweden 6 Institute of Molecular Genetics, Consiglio Nazionale delle Ricerche (CNR), 27100 Pavia, Italy 7 Department of Biotechnologial Research (DIBIT), San Raffaele Scientific Institute, 20132 Milano, Italy 8 Department of Cell Biology, University of CT Health Center, Farmington, CT 06030, USA
* To whom correspondence should be addressed at: Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden. Tel: +46 186112799; Fax: +46 18554025; Email: niklas.dahl{at}genpat.uu.se
Received July 13, 2008; Accepted August 29, 2008
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.
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