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In Vitro Coexpression and Pharmacological Rescue of Mutant Gonadotropin-Releasing Hormone Receptors Causing Hypogonadotropic Hypogonadism in Humans Expressing Compound Heterozygous Alleles

Research Unit in Reproductive Medicine (A.L.-M., A.U.-A., P.M.C.), Instituto Mexicano del Seguro Social, México D.F. 10101, Mexico; Divisions of Neuroscience and Reproductive Biology (A.L.-M., J.A.J., P.M.C., A.U.-A.), Oregon National Primate Research Center, Beaverton, Oregon 97006; and Department of Physiology and Pharmacology and Cell and Developmental Biology, Oregon Health and Science University (P.M.C.), Portland, Oregon 97239

Address all correspondence and requests for reprints to: P. Michael Conn, Oregon National Primate Research Center/Oregon Health and Science University, 5050 NW 185th Avenue, Beaverton, Oregon 97006. E-mail: connm{at}ohsu.edu; or Alfredo Leaños-Miranda, Research Unit in Reproductive Medicine, Instituto Mexicano del Seguro Social, Apdo. Postal 99–065, Unidad Independencia, México D.F., C.P. 10101, México. E-mail: alfredo{at}intranet.com.mx.

We analyzed the function of mutant GnRH receptor (GnRHR) pairs associated with compound heterozygous patients showing complete or partial forms of hypogonadotropic hypogonadism. We did this to examine potential interactions between misfolded mutants that may influence net receptor function and response to pharmacological rescue. Nine pairs of GnRHR mutants and an unreported combination (L³¹⁴X_(stop)/R²⁶²Q) were studied. Coexpression of each pair of mutants in COS-7 cells resulted in an active predominant effect (Q¹⁰⁶R/L²⁶⁶R, A¹⁷¹T/Q¹⁰⁶R, T³²I/C²⁰⁰Y, and R²⁶²Q/A¹²⁹D mutant GnRHR pairs), an additive effect (R²⁶²Q/Q¹⁰⁶R, N¹⁰K/Q¹⁰⁶R, and R²⁶²Q/Y²⁸⁴C human GnRHR pairs), or a dominant-negative effect (L³¹⁴X_(stop)/Q¹⁰⁶R, Q¹⁰⁶R+S²¹⁷R/R²⁶²Q, and L³¹⁴X_(stop)/R²⁶²Q GnRHRs). For all combinations, addition of the pharmacoperone IN3 increased both agonist binding and effector coupling. The IN3 response was unpredictable because responses could be either similar, higher, or lower, compared with that exhibited by the less affected mutant. The clinical phenotype in patients expressing complex heterozygous alleles appears to be dictated by both the contribution from each mutant and a dominant-negative effect similar to that reported for mutants and wild-type receptor. Depending on the genotype, partial or full restoration of receptor function in response to pharmacological chaperones may be achievable goals in patients bearing inactivating mutations in the GnRHR gene.

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