TACR3 – Kallmann syndrome

TACR3 variants have been identified in a limited number of Kallmann syndrome (KS) patients, generally in combination with mutations in other genes. In a cohort of 168 IHH/KS probands, two unrelated KS patients harbored heterozygous TACR3 c.824G>A (p.Trp275Ter) alongside NELF mutations, with no evidence of segregation or monogenic inheritance (PMID:21300340). Monogenic TACR3 variants causing KS have not been reported.

Functional studies demonstrate that missense NK3R mutations (p.His148Leu, p.Tyr256His, p.Y315C, p.R295S) impair receptor trafficking, stability, and Gq-protein signaling, confirming a loss-of-function mechanism (PMID:19755480; PMID:24376026). Despite robust evidence for TACR3 in normosmic IHH, its direct role in anosmic hypogonadotropic hypogonadism remains unsubstantiated. Clinically, TACR3 testing in KS offers limited utility beyond comprehensive gene panels.

Key take-home: TACR3 contributes minimally to KS and is best assessed as part of multigene screening.

References

• Fertility and Sterility • 2011 • Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome. PMID:21300340
• The Journal of clinical endocrinology & metabolism • 2009 • Hypogonadotropic hypogonadism due to a novel missense mutation in the first extracellular loop of the neurokinin B receptor. PMID:19755480
• FASEB journal • 2014 • TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH-deficient patients. PMID:24376026

Evidence Based Scoring (AI generated)