GNRH1 – Idiopathic Hypogonadotropic Hypogonadism

GNRH1 encodes gonadotropin-releasing hormone 1 (GnRH1), the decapeptide driving pituitary gonadotropin secretion. Pathogenic GNRH1 variants disrupt GnRH production or function, leading to idiopathic hypogonadotropic hypogonadism (MONDO:0018555), characterized by failed pubertal development, infertility, delayed puberty, and primary amenorrhea ([PMID:19535795]; [PMID:23936060]).

A homozygous frameshift variant, c.18dup (p.Leu7fs), was identified in two affected siblings from a consanguineous family with normosmic IHH; parents and an unaffected sibling were heterozygous carriers. In vitro expression showed absence of immunoreactive GnRH, confirming autosomal recessive LoF ([PMID:19535795]).

A recurrent missense change, c.91C>T (p.Arg31Cys), was found heterozygous in nine nCHH patients across four unrelated families, implicating a dominant mode of pathogenicity. All carriers displayed absent or delayed puberty and infertility, supporting a gain-of-function or dominant-negative mechanism ([PMID:23936060]).

Functional assays of p.Arg31Cys GnRH revealed dramatic reduction in receptor binding, MAPK signaling, inositol phosphate accumulation, intracellular calcium mobilization, and LHβ transcription, confirming peptide LoF ([PMID:23936060]).

The c.18dup and similar frameshift alleles abrogate the conserved decapeptide, resulting in complete loss of hormone production and failure to trigger downstream endocrine responses ([PMID:19535795]).

Genetic screening in additional IHH cohorts failed to detect GNRH1 coding mutations ([PMID:12788881]; [PMID:15546906]), indicating that GNRH1 defects account for ~1–2% of IHH cases. However, the combination of AR and AD pedigrees with robust functional concordance supports a strong gene–disease relationship.

Key take-home: GNRH1 LoF variants present a clinically actionable cause of idiopathic hypogonadotropic hypogonadism, warranting inclusion in diagnostic gene panels to guide early GnRH therapy and fertility management.

References

• The New England Journal of Medicine • 2009 • Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. PMID:19535795
• PLoS One • 2013 • R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism. PMID:23936060
• 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

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