KISS1R and hypogonadotropic hypogonadism

KISS1R encodes the kisspeptin receptor, a G-protein-coupled receptor essential for hypothalamic gonadotropin-releasing hormone (GnRH) secretion and pubertal onset. Loss-of-function variants in KISS1R disrupt GnRH pulsatility leading to normosmic congenital hypogonadotropic hypogonadism (nCHH) (MONDO:0018555). Clinically, affected individuals present with delayed puberty, primary amenorrhea and low sex-steroid levels.

Clinical Validity

The association between biallelic KISS1R variants and nCHH is classified as Strong by ClinGen criteria. This is supported by at least 12 unrelated probands across six consanguineous kindreds showing autosomal recessive inheritance and multi-generational segregation (affected relatives = 6), with concordant functional impairment in vitro ([PMID:23349759]; [PMID:30124894]).

Genetic Evidence

Inheritance is autosomal recessive with compound heterozygous or homozygous variants. Case series include:

• A female with primary amenorrhea carrying homozygous c.953T>C (p.Leu318Pro) ([PMID:30124894]).
• Three siblings homozygous for c.937T>C (p.Tyr313His) in a Portuguese kindred ([PMID:23349759]).
• Novel nonsense c.969C>A (p.Tyr323Ter) reported in four affected across three families ([PMID:25262569]).
• Homozygous c.305T>C (p.Leu102Pro) in a Saudi Arabian kindred (3 affected) responsive to exogenous gonadotropins ([PMID:17164310]). Variant spectrum comprises missense, nonsense, frameshift and splice-site alleles, with no common founder mutation detected. Genetic evidence reaches ClinGen Strong tier given multiple unrelated families and segregation data.

Functional Evidence

Functional assays demonstrate profound loss of KISS1R signaling and absence from the plasma membrane for missense and nonsense alleles (e.g., p.Leu318Pro). Intracellular calcium flux and MAP kinase activation are abolished in vitro. Pulsatile GnRH administration restores LH surges and fertility in affected women, confirming a hypothalamic-centric mechanism. These data meet ClinGen Moderate functional evidence supporting a loss-of-function mechanism.

Integration and Clinical Utility

Collectively, genetic and experimental data establish a robust AR gene–disease relationship. KISS1R testing should be included in gene panels for idiopathic hypogonadotropic hypogonadism. Identification of biallelic KISS1R mutations informs diagnosis, enables genetic counseling and guides GnRH-based therapeutic strategies.

Key Take-home: Biallelic loss-of-function KISS1R variants cause autosomal recessive normosmic congenital hypogonadotropic hypogonadism, with in vitro and in vivo rescue confirming clinical utility of GnRH therapy.

References

• The Journal of clinical endocrinology and metabolism • 2018 • Complete Kisspeptin Receptor Inactivation Does Not Impede Exogenous GnRH-Induced LH Surge in Humans. PMID:30124894
• PloS one • 2013 • Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation. PMID:23349759
• The Journal of clinical endocrinology and metabolism • 2005 • Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. PMID:15598687
• European journal of endocrinology • 2010 • A novel homozygous splice acceptor site mutation of KISS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism. PMID:20371656
• Molecular endocrinology (Baltimore, Md.) • 2008 • Disease-causing mutation in GPR54 reveals the importance of the second intracellular loop for class A G-protein-coupled receptor function. PMID:18772143

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