Abstract
Context TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). In the absence of animal models, studies of human neuroendocrine phenotypes associated with neurokinin B and NK3R receptor dysfunction can help to decipher the pathophysiology of this signaling pathway.ObjectiveTo evaluate the prevalence of TAC3/TACR3 mutations, characterize novel TACR3 mutations and to analyze neuroendocrine profiles in nCHH caused by deleterious TAC3/TACR3 biallelic mutations.ResultsFrom a cohort of 352 CHH, we selected 173 nCHH patients and identified nine patients carrying TAC3 or TACR3 variants (5.2%). We describe here 7 of these TACR3 variants (1 frameshift and 2 nonsense deleterious mutations and 4 missense variants) found in 5 subjects. Modeling and functional studies of the latter demonstrated the deleterious consequence of one missense mutation (Tyr267Asn) probably caused by the misfolding of the mutated NK3R protein.We found a statistically significant (p<0.0001) higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2. Three patients with TAC3/TACR3 biallelic mutations had an apulsatile LH profile but low-frequency alpha-subunit pulses. Pulsatile GnRH administration increased alpha-subunit pulsatile frequency and reduced the FSH/LH ratio.ConclusionThe gonadotropin axis dysfunction associated with nCHH due to TAC3/TACR3 mutations is related to a low GnRH pulsatile frequency leading to a low frequency of alpha-subunit pulses and to an elevated FSH/LH ratio. This ratio might be useful for pre-screening nCHH patients for TAC3/TACR3 mutations.
Highlights
In the last two years, loss-of-function mutations in TAC3 (MIM 162330) and TACR3 (MIM 162332), the genes encoding neurokinin B (NKB) and its receptor NK3R, respectively, have been described in patients with non syndromic normosmic congenital hypogonadotropic hypogonadism (OMIM #146110), pointing to a fundamental role of this pathway in the physiology of the human gonadotrope axis [1,2,3,4,5]
Detailed neuroendocrine studies of adult normosmic congenital hypogonadotropic hypogonadism (nCHH) patients with TAC3/TACR3 mutations may help to decipher the role of this signaling pathway in the pathophysiology of the gonadotrope axis
Case reports In family 1, three sisters were affected
Summary
In the last two years, loss-of-function mutations in TAC3 (MIM 162330) and TACR3 (MIM 162332), the genes encoding neurokinin B (NKB) and its receptor NK3R, respectively, have been described in patients with non syndromic normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110), pointing to a fundamental role of this pathway in the physiology of the human gonadotrope axis [1,2,3,4,5]. In rodents [7], sheep [8,9], goat [10] and non human primates [11], NKB is expressed throughout the brain [12] and by the same neurons that express kisspeptin and dynorphin. In rats, these neurons form a bilateral, interconnected network that projects to NK3R-expressing GnRH terminals in the median eminence [13]. Detailed neuroendocrine studies of adult nCHH patients with TAC3/TACR3 mutations may help to decipher the role of this signaling pathway in the pathophysiology of the gonadotrope axis
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