TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans

• Published in: The journal of clinical endocrinology and metabolism Vol. 95; no. 5; pp. 2287 - 2295
• Main Authors: Young, Jacques, Bouligand, Jerome, Francou, Bruno, Raffin-Sanson, Marie-Laure, Gaillez, Stephanie, Jeanpierre, Marc, Grynberg, Michael, Kamenicky, Peter, Chanson, Philippe, Brailly-Tabard, Sylvie, Guiochon-Mantel, Anne
• Format: Journal Article Web Resource
• Language: English
• Published: Bethesda, MD Endocrine Society 01.05.2010; Oxford University Press; Copyright by The Endocrine Society
• Subjects: Adult; Amenorrhea - genetics; Amino Acid Substitution; Biological and medical sciences; Breast - growth & development; Consanguinity; Endocrinopathies; Feeding. Feeding behavior; Female; Follicle Stimulating Hormone - blood; Follicle-stimulating hormone; Fundamental and applied biological sciences. Psychology; Gene Deletion; genetic processes; Genetics; Genetics & genetic processes; Gonadotropin-releasing hormone; Gonadotropins; Génétique & processus génétiques; Haplotypes; Homozygote; Humans; Hypogonadism; Hypogonadism - genetics; Hypogonadism - physiopathology; Hypogonadism/genetics/physiopathology; Hypothalamus; Hypothalamus. Hypophysis. Epiphysis (diseases); Introns - genetics; Life sciences; Luteinizing hormone; Luteinizing Hormone - blood; Male; Medical sciences; Mutation; Mutation, Missense; Neurokinin; Neurokinin B; Neurokinin B - genetics; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Pedigree; Penis - abnormalities; Pituitary (anterior); Receptors, Neurokinin-3 - genetics; Sciences du vivant; Steroid hormones; Testosterone - blood; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Endocrinopathy; Human; Hypogonadotropic hypogonadism; Obesity; Congenital; Nutrition; Hypothalamic diseases; Nutrition disorder; Metabolic diseases; Congenital disease; Genital diseases; Cause; Defect; Endocrinology; Nutritional status
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2009-2600

Context: Missense loss-of-function mutations in TAC3 and TACR3, the genes encoding neurokinin B and its receptor NK3R, respectively, were recently discovered in kindreds with nonsyndromic normosmic congenital hypogonadotropic hypogonadism (CHH), thus identifying a fundamental role of this pathway in the human gonadotrope axis. Objective: The objective of the study was to investigate the consequences on gonadotrope axis of TAC3 deletion and TACR3 truncation in adult patients with normosmic complete CHH. Results: We identified three unrelated patients with the same homozygous substitution in the TAC3 intron 3 acceptor splicing site (c.209-1G>C) and three siblings who bore a homozygous mutation in the TACR3 intron 2 acceptor splicing site (c.738-1G>A). We demonstrated that these two mutations, respectively, deleted neurokinin B and truncated its receptor NK3R. We found in three patients with TAC3 mutation originating from Congo and Haiti a founding event in a more distant ancestor by means of haplotype analysis. We calculated that time to this common ancestor was approximately 21 generations. In several patients we observed a dissociation between the very low LH and normal or nearly normal FSH levels, this gonadotropin responding excessively to the GnRH challenge test. This particular hormonal profile, suggests the possibility of a specific neuroendocrine impairment in patients with alteration of neurokinin B signaling. Finally, in these patients, pulsatile GnRH administration normalized circulating sex steroids, LH release, and restored fertility in one subject. Conclusion: Our data demonstrate the hypothalamic origin of the gonadotropin deficiency in these genetic forms of normosmic CHH. Neurokinin B and NK3R therefore both play a crucial role in hypothalamic GnRH release in humans.