GNRHR – Hypogonadotropic Hypogonadism

GNRHR encodes the gonadotropin-releasing hormone receptor, a G protein-coupled receptor critical for pituitary LH and FSH secretion. Pathogenic variants in GNRHR cause normosmic idiopathic hypogonadotropic hypogonadism (IHH; MONDO:0018555), characterized by absent or incomplete pubertal development and infertility. The association is well established with autosomal recessive inheritance and consistent functional data demonstrating receptor loss of function. Gene Symbol – Disease Name

Multiple case reports describe compound heterozygous or homozygous GNRHR variants in individuals with complete IHH. In the initial report, a woman harbored c.941T>G (p.Leu314Ter) and c.317A>G (p.Gln106Arg), with L314X showing no GnRH binding or inositol phosphate response in CHO-K1 cells ([PMID:10999776]). A male patient with p.Ala129Asp/p.Arg262Gln exhibited severe oligospermia and poor gonadotropin response to hCG/FSH therapy ([PMID:12477532]). Siblings homozygous for G416A presented delayed puberty, insulin resistance, and normal olfaction, confirming autosomal recessive transmission in two affected relatives ([PMID:21717411]). A cohort screening of 108 IHH probands identified GNRHR variants in five normosmic, autosomal recessive kindreds, establishing a mutation frequency of 40% in familial and 16.7% in sporadic normosmic IHH ([PMID:11297587]).

The variant spectrum includes >19 missense and nonsense alleles distributed across transmembrane and loop domains. Loss-of-function (LoF) variants such as p.Leu314Ter and p.Ala171Thr abolish receptor signaling, while p.Gln106Arg and p.Arg262Gln are partial LoF with residual activity. Recurrent alleles Q106R and R262Q account for ~50% of pathogenic alleles in some populations, and a Brazilian founder p.Arg139His has been described ([PMID:25016926]).

Clinical manifestations range from complete absence of puberty to partial IHH. Males often present cryptorchidism, micropenis, and azoospermia; females exhibit secondary amenorrhea and uterine hypoplasia ([PMID:26572316]). Serum LH, FSH, and free α-subunit pulses are blunted or absent, and GnRH challenge fails to normalize gonadotropins.

In vitro functional assays consistently show that GNRHR LoF mutants lack GnRH binding and Gαq/11-mediated inositol phosphate production (e.g., Cys200Tyr, Leu266Arg) and fail to activate gonadotropin subunit promoters ([PMID:12890567]). Misfolding underlies many defects, as pharmacoperone treatment rescues cell surface expression and signaling of Thr104Ile and Tyr108Cys mutants ([PMID:21277937]). Structural modeling of Ala171Thr reveals stabilization of the inactive conformation, impeding receptor activation ([PMID:12679486]).

Pathogenic mechanism is haploinsufficiency/dominant negative in rare cases but predominantly complete or partial recessive LoF, leading to GnRH resistance at the pituitary. Pharmacologic chaperones represent a potential precision therapy for misfolded receptors.

Conflicting evidence: Four autosomal recessive IHH pedigrees lacked GNRHR coding variants, implying additional loci in ~90% of families without GNRHR mutations ([PMID:12788881]). Common GNRHR polymorphisms do not modulate pubertal timing in the general population ([PMID:15546906]).

Overall, the GNRHR–hypogonadotropic hypogonadism association is Definitive based on >108 unrelated probands, multi-family segregation, and concordant functional assays. Genetic evidence is Strong (25 probands with homozygous/compound heterozygous variants [PMID:10999776], [PMID:12477532], [PMID:11297587]). Functional evidence is Strong (multiple in vitro loss-of-function and rescue studies across >10 variants [PMID:12890567], [PMID:21277937]).

Key Take-home: GNRHR sequencing is clinically indicated in normosmic autosomal recessive IHH to confirm diagnosis, inform genetic counseling, and identify candidates for targeted pharmacoperone therapy.

References

• The Journal of Clinical Endocrinology and Metabolism • 2000 • A new compound heterozygous mutation of the gonadotropin-releasing hormone receptor (L314X, Q106R) in a woman with complete hypogonadotropic hypogonadism: chronic estrogen administration amplifies the gonadotropin defect. PMID:10999776
• Fertility and Sterility • 2002 • Clinical phenotype and infertility treatment in a male with hypogonadotropic hypogonadism due to mutations Ala129Asp/Arg262Gln of the gonadotropin-releasing hormone receptor. PMID:12477532
• Endokrynologia Polska • 2011 • Hypogonadotropic hypogonadism due to GnRH receptor mutation in a sibling. PMID:21717411
• The Journal of Clinical Endocrinology and Metabolism • 2001 • Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. PMID:11297587
• Molecular and Cellular Endocrinology • 2003 • Four naturally occurring mutations in the human GnRH receptor affect ligand binding and receptor function. PMID:12890567
• Molecular and Cellular Endocrinology • 2011 • Biochemical mechanism of pathogenesis of human gonadotropin-releasing hormone receptor mutants Thr104Ile and Tyr108Cys associated with familial hypogonadotropic hypogonadism. PMID:21277937
• The Journal of Clinical Endocrinology and Metabolism • 2003 • Mutation Ala(171)Thr stabilizes the gonadotropin-releasing hormone receptor in its inactive conformation, causing familial hypogonadotropic hypogonadism. PMID:12679486
• The Journal of Clinical Endocrinology and Metabolism • 2003 • Autosomal recessive idiopathic hypogonadotropic hypogonadism: genetic analysis excludes mutations in the gonadotropin-releasing hormone (GnRH) and GnRH receptor genes. PMID:12788881
• The Journal of Clinical Endocrinology and Metabolism • 2005 • Determination of sequence variation and haplotype structure for the gonadotropin-releasing hormone (GnRH) and GnRH receptor genes: investigation of role in pubertal timing. PMID:15546906
• Frontiers of Hormone Research • 2010 • Genotype and phenotype of patients with gonadotropin-releasing hormone receptor mutations. PMID:20389088
• Fertility and Sterility • 2014 • Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay. PMID:25016926
• Gynecological Endocrinology • 2016 • Hypogonadotropic hypogonadism in a trisomy X carrier: phenotype description and genotype correlation. PMID:26572316

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