Toward gene therapy of primary ovarian failure: Adenovirus expressing human FSH receptor corrects the Finnish C566T mutation

M. Ghadami, S. A. Salama, N. Khatoon, R. Chilvers, M. Nagamani, P. J. Chedrese, A. Al-Hendy

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Abstract

Resistance ovarian syndrome is a heterogeneous disorder inherited as a Mendelian recessive trait and characterized by infertility, primary amenorrhea, normal karyotype and elevated serum FSH and LH levels. An inactivating mutation, C566T, in FSH receptor gene (FSHR) has been identified initially in Finland. We investigated if an adenovirus expressing a normal copy of human FSHR (Ad-hFSHR) has the ability to: (i) transfect granulosa cell lines, (ii) render the transfected cell lines responsive to FSH stimulation and (iii) transcomplement the malfunctioning form of human FSHR gene with C566T mutation. COS-7, JC-410, JC-410-P450-scc-luc and JC-410-StAR-luc cell lines were infected by Ad-hFSHR followed by treatment with FSH. Functional activity of the Ad-hFSHR was tested by measuring cyclic adenosine monophosphate (cAMP) or luciferase activity in response to FSH stimulation, and showed 2-4.6-fold increases in Ad-hFSHR transfected cells compared with untransfected or Ad-LacZ transfected cells, indicating that Ad-hFSHR is functionally active and expressing hFSHR. Generation of cAMP in cells expressing only mutated hFSHR-T566 showed minimal increase after FSH stimulation. Co-transfection of Ad-hFSHR in these cells carrying the malfunction form of human FSHR caused significant increases of 2.2-7.4-fold in FSH dependent cAMP generation (P = 0.0007). We concluded that adenovirus expressing a normal human FSHR can compensate the inactivating human FSHR-C566T mutation and restore FSH responsiveness.

Original languageEnglish (US)
Pages (from-to)9-15
Number of pages7
JournalMolecular Human Reproduction
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2008

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Keywords

  • Finnish C566T mutation
  • Follicle-stimulating hormone receptor
  • Gene therapy of ovarian failure
  • Infertility
  • Primary amenorrhea

ASJC Scopus subject areas

  • Reproductive Medicine
  • Embryology
  • Molecular Biology
  • Genetics
  • Obstetrics and Gynecology
  • Developmental Biology
  • Cell Biology

Cite this

Ghadami, M., Salama, S. A., Khatoon, N., Chilvers, R., Nagamani, M., Chedrese, P. J., & Al-Hendy, A. (2008). Toward gene therapy of primary ovarian failure: Adenovirus expressing human FSH receptor corrects the Finnish C566T mutation. Molecular Human Reproduction, 14(1), 9-15. https://doi.org/10.1093/molehr/gam077