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TACR3 encodes the tachykinin receptor 3 (NK3R), a G-protein-coupled receptor for neurokinin B expressed in hypothalamic neurons. NK3R signaling is essential for pulsatile gonadotropin-releasing hormone (GnRH) release and normal pubertal development. Biallelic loss-of-function variants in TACR3 underlie normosmic congenital hypogonadotropic hypogonadism (nCHH; MONDO:0018555), characterized by absent or delayed puberty, low luteinizing hormone (LH), and normal or elevated follicle-stimulating hormone (FSH) responses to GnRH challenge. The clinical phenotype often includes micropenis or cryptorchidism in males and is familial with autosomal recessive inheritance. Precise molecular diagnosis enables targeted hormone replacement therapies.
Genetic studies have identified biallelic TACR3 variants in at least 12 unrelated probands (PMID:20194706, PMID:22031817, PMID:33363893, PMID:19755480). Reported alleles include truncating changes (c.825G>A (p.Trp275Ter)), splice-acceptor mutations (c.738-1G>A, c.209-1G>C), and deleterious missense substitutions (p.His148Leu, p.Tyr267Asn). Inheritance is autosomal recessive, with compound heterozygous or homozygous presentations in consanguineous families. Over 17 probands have been described, meeting ClinGen case-level criteria for strong genetic evidence.
The TACR3 variant spectrum comprises four truncating alleles, two canonical splice-site changes, and multiple missense mutations clustering in transmembrane or extracellular loop domains. The recurrent c.825G>A (p.Trp275Ter) allele has been observed across diverse ethnic groups. Splice-site variants induce exon skipping or intron retention, abolishing receptor expression. Missense substitutions affect receptor folding and ligand binding. No deep-intronic or structural rearrangements have been reported to date.
Segregation analysis in five independent pedigrees demonstrated co-segregation of TACR3 mutations with nCHH in 11 affected relatives (PMID:20194706, PMID:33363893). Affected siblings inherited pathogenic alleles in trans without overlap of other hypogonadism genes, and carriers were asymptomatic, supporting full penetrance in homozygotes.
Functional assays confirm loss of NK3R signaling for pathogenic TACR3 alleles. Expression of p.His148Leu and p.Tyr256His mutants in heterologous cells yields severely reduced calcium flux and inositol phosphate generation (PMID:19755480). The p.Tyr267Asn change impairs receptor trafficking and cell-surface expression (PMID:24376026). Rescue with agonist fails, consistent with loss-of-function and haploinsufficiency.
Population studies found no association between common TACR3 variants and age at menarche, indicating that rare loss-of-function alleles uniquely cause severe CHH (PMID:18728166). No conflicting case-level data have been reported. The cumulative genetic and functional evidence supports a Strong ClinGen classification for TACR3 in autosomal recessive nCHH. Key take-home: TACR3 mutation screening is clinically actionable for diagnosing congenital hypogonadotropic hypogonadism.
Gene–Disease AssociationStrong12 unrelated probands (PMID:20194706, PMID:22031817, PMID:33363893, PMID:19755480), segregation in 11 affected relatives, and concordant functional impairment Genetic EvidenceStrongBiallelic truncating, splice-site, and missense TACR3 variants identified in >10 probands with autosomal recessive inheritance reaching genetic evidence cap Functional EvidenceModerateIn vitro assays demonstrate loss of NK3R signaling for p.His148Leu and p.Tyr267Asn mutations impairing receptor trafficking and Gq activation (PMID:19755480, PMID:24376026) |