GNRHR – hypogonadotropic hypogonadism 7 with or without anosmia

Hypogonadotropic hypogonadism 7 with or without anosmia is characterized by deficient gonadotropin-releasing hormone receptor signaling resulting in absent or delayed puberty and infertility. The GNRHR gene encodes the pituitary GnRH receptor, which is essential for luteinizing hormone and follicle-stimulating hormone secretion. Pathogenic GNRHR variants cause autosomal recessive normosmic idiopathic hypogonadotropic hypogonadism (IHH). Phenotypes range from complete GnRH resistance with absent pulsatility to partial responsiveness to pulsatile GnRH or exogenous gonadotropins. The association between GNRHR and IHH was first reported in 2002 and has since been replicated across multiple families and functional studies, supporting a ClinGen Definitive classification.

Numerous homozygous and compound heterozygous mutations in GNRHR have been identified in IHH patients. In the original report, a woman with primary amenorrhea and absent thelarche harbored a novel homozygous splice acceptor site mutation c.523-1G>A causing exon 2 skipping (PMID:12050282). Subsequent studies described compound heterozygous missense variants c.31C>A (p.Gln11Lys) together with c.959C>T (p.Pro320Leu) in a normosmic female (PMID:15240592), and homozygous transition c.416G>A (p.Arg139His) in siblings from a consanguineous family (PMID:21717411). A Chinese pedigree revealed a novel homozygous missense variant c.364C>T (p.Leu122Phe) in prepubertal boys with cryptorchidism and micropenis (PMID:29777911). Segregation analysis in four families demonstrated autosomal recessive inheritance with unaffected heterozygous carriers, totaling seven probands to date.

The variant spectrum includes splice site and missense mutations that abrogate receptor function. The splice acceptor variant c.523-1G>A induces exon 2 skipping and a premature stop codon (PMID:12050282). Missense alleles affecting ligand binding or conformation—c.31C>A (p.Gln11Lys), c.959C>T (p.Pro320Leu), c.416G>A (p.Arg139His), c.364C>T (p.Leu122Phe)—lead to defective GnRH binding or trafficking (PMID:15240592, PMID:21717411, PMID:29777911). No recurrent founder variants have been widely observed, underscoring allelic heterogeneity.

Functional assays confirm that these mutations cause loss of receptor signaling. Mutants such as p.Gln106Arg and p.Arg262Gln impair inositol phosphate production and reduce FSHβ and LHβ promoter activation (PMID:12574221). The p.Ala171Thr substitution stabilizes the inactive receptor conformation, abolishing GnRH-induced phospholipase C activity (PMID:12679486). Variants like Leu266Arg and Cys279Tyr fail to exhibit specific GnRH binding or elicit downstream signaling (PMID:12890567). Pharmacoperone rescue studies further demonstrate misfolding as a pathogenic mechanism and offer potential therapeutic strategies (PMID:12606630). In patient-derived cells, the c.364C>T variant shows absent calcium mobilization, confirming complete loss-of-function (PMID:29777911).

Clinically, GNRHR-related IHH presents as normosmic IHH with a spectrum from complete GnRH resistance (primary amenorrhea, absent secondary sexual development, no gonadotropin pulsatility) to partial phenotypes responsive to pulsatile GnRH or gonadotropin therapy. Ovulation induction and successful fertility outcomes have been achieved in LoF cases (PMID:12050282). Genotype–phenotype correlations are imperfect, with some variants yielding reversible IHH or milder presentations. Early genetic diagnosis enables timely initiation of hormone replacement and fertility management. GNRHR mutation screening should be integral to the diagnostic work-up of normosmic IHH, especially in familial or consanguineous scenarios.

References

• The Journal of clinical endocrinology and metabolism • 2002 • Novel homozygous splice acceptor site GnRH receptor (GnRHR) mutation: human GnRHR "knockout". PMID:12050282
• The Journal of clinical endocrinology and metabolism • 2004 • GNRHR mutations in a woman with idiopathic hypogonadotropic hypogonadism highlight the differential sensitivity of luteinizing hormone and follicle-stimulating hormone to gonadotropin-releasing hormone. PMID:15240592
• Endokrynologia Polska • 2011 • Hypogonadotropic hypogonadism due to GnRH receptor mutation in a sibling. PMID:21717411
• Gene • 2018 • Deficiency in GnRH receptor trafficking due to a novel homozygous mutation causes idiopathic hypogonadotropic hypogonadism in three prepubertal siblings. PMID:29777911
• The Journal of clinical endocrinology and metabolism • 2003 • Two common naturally occurring mutations in the human gonadotropin-releasing hormone (GnRH) receptor have differential effects on gonadotropin gene expression and on GnRH-mediated signal transduction. PMID:12574221
• 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
• Molecular and cellular endocrinology • 2003 • Four naturally occurring mutations in the human GnRH receptor affect ligand binding and receptor function. PMID:12890567
• The Journal of pharmacology and experimental therapeutics • 2003 • Structure-activity relations of successful pharmacologic chaperones for rescue of naturally occurring and manufactured mutants of the gonadotropin-releasing hormone receptor. PMID:12606630

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