TAC3 – Normosmic Hypogonadotropic Hypogonadism

Normosmic congenital hypogonadotropic hypogonadism (nCHH) is characterized by absent puberty with normal olfaction and has been attributed to autosomal recessive loss-of-function variants in TAC3. Five probands in three unrelated kindreds have biallelic TAC3 variants, supporting a strong gene–disease relationship (PMID:20194706, PMID:20332248).

Inheritance is autosomal recessive, with the recurrent intronic variant c.209-1G>C homozygous in three unrelated patients and segregating with disease in kindreds (PMID:20194706).

Case series identify multiple variant classes in TAC3: two splice-site mutations (c.209-1G>C, c.238+1G>C) abolish neurokinin B synthesis, and a missense variant c.187G>C (p.Ala63Pro) has been reported in an isolated nIHH patient (PMID:23329188).

Functional studies demonstrate that splicing mutations eliminate mature neurokinin B, resulting in low GnRH pulsatility and an elevated FSH/LH ratio that normalizes with pulsatile GnRH therapy, confirming a hypothalamic mechanism (PMID:20194706, PMID:20332248).

Population studies of common TAC3 variants show no significant association with age at menarche in the general population, arguing against a subtler modulatory effect (PMID:18728166).

Together, genetic and mechanistic data establish TAC3 biallelic loss-of-function as a strong cause of nCHH, warranting inclusion of TAC3 in diagnostic gene panels for congenital hypogonadotropic hypogonadism.

References

• The Journal of clinical endocrinology and metabolism • 2010 • TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans. PMID:20194706
• PLoS One • 2011 • Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations. PMID:22031817
• The Journal of clinical endocrinology and metabolism • 2010 • TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. PMID:20332248
• The Journal of clinical endocrinology and metabolism • 2008 • Association studies of common variants in 10 hypogonadotropic hypogonadism genes with age at menarche. PMID:18728166
• Arquivos brasileiros de endocrinologia e metabologia • 2012 • Mutational analysis of TAC3 and TACR3 genes in patients with idiopathic central pubertal disorders. PMID:23329188

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