Distribution of Gene Mutations Associated with Familial Normosmic Idiopathic Hypogonadotropic Hypogonadism

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Abstract

Objective: Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is characterized by failure of initiation or maintenance of puberty due to insufficient gonadotropin release, which is not associated with anosmia/hyposmia. The objective of this study was to determine the distribution of causative mutations in a hereditary form of nIHH.

Methods: In this prospective collaborative study, 22 families with more than one affected individual (i.e. multiplex families) with nIHH were recruited and screened for genes known or suspected to be strong candidates for nIHH.

Results: Mutations were identified in five genes (GNRHR, TACR3, TAC3, KISS1R, and KISS1) in 77% of families with autosomal recessively inherited nIHH. GNRHR and TACR3 mutations were the most common two causative mutations occurring with about equal frequency.

Conclusions: Mutations in these five genes account for about three quarters of the causative mutations in nIHH families with more than one affected individual. This frequency is significantly greater than the previously reported rates in all inclusive (familial plus sporadic) cohorts. GNRHR and TACR3 should be the first two genes to be screened for diagnostic purposes. Identification of causative mutations in the remaining families will shed light on the regulation of puberty.

Conflict of interest:None declared.

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TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction.

A. Kemal Topaloglu, Frank Reimann, Metin Guclu … (2009)

The timely secretion of gonadal sex steroids is essential for the initiation of puberty, the postpubertal maintenance of secondary sexual characteristics and the normal perinatal development of male external genitalia. Normal gonadal steroid production requires the actions of the pituitary-derived gonadotropins, luteinizing hormone and follicle-stimulating hormone. We report four human pedigrees with severe congenital gonadotropin deficiency and pubertal failure in which all affected individuals are homozygous for loss-of-function mutations in TAC3 (encoding Neurokinin B) or its receptor TACR3 (encoding NK3R). Neurokinin B, a member of the substance P-related tachykinin family, is known to be highly expressed in hypothalamic neurons that also express kisspeptin, a recently identified regulator of gonadotropin-releasing hormone secretion. These findings implicate Neurokinin B as a critical central regulator of human gonadal function and suggest new approaches to the pharmacological control of human reproduction and sex hormone-related diseases.

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TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood.

Jane Stewart, Kelly T. Hughes, Gough Au … (2010)

Mutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH), but broader populations have not yet been tested and genotype-phenotype correlations have not been established. A broad cohort of normosmic IHH probands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. The study consisted of sequencing of TAC3/TACR3, in vitro functional assays, and neuroendocrine phenotyping conducted in tertiary care centers worldwide. 345 probands, 18 family members, and 292 controls were studied. Reproductive phenotypes throughout reproductive life and before and after therapy were examined. Rare sequence variants in TAC3/TACR3 were detected. In TACR3, 19 probands harbored 13 distinct coding sequence rare nucleotide variants [three nonsense mutations, six nonsynonymous, four synonymous (one predicted to affect splicing)]. In TAC3, one homozygous single base pair deletion was identified, resulting in complete loss of the neurokinin B decapeptide. Phenotypic information was available on 16 males and seven females with coding sequence variants in TACR3/TAC3. Of the 16 males, 15 had microphallus; none of the females had spontaneous thelarche. Seven of the 16 males and five of the seven females were assessed after discontinuation of therapy; six of the seven males and four of the five females demonstrated evidence for reversibility of their hypogonadotropism. Mutations in the neurokinin B pathway are relatively common as causes of hypogonadism. Although the neurokinin B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time.

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Inactivating KISS1 mutation and hypogonadotropic hypogonadism.

Fatih Gürbüz, Bilgin Yuksel, J. Ignacio Tello … (2012)

Gonadotropin-releasing hormone (GnRH) is the central regulator of gonadotropins, which stimulate gonadal function. Hypothalamic neurons that produce kisspeptin and neurokinin B stimulate GnRH release. Inactivating mutations in the genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), neurokinin B (TAC3), and the neurokinin B receptor (TACR3) result in pubertal failure. However, human kisspeptin loss-of-function mutations have not been described, and contradictory findings have been reported in Kiss1-knockout mice. We describe an inactivating mutation in KISS1 in a large consanguineous family that results in failure of pubertal progression, indicating that functional kisspeptin is important for puberty and reproduction in humans. (Funded by the Scientific and Technological Research Council of Turkey [TÜBİTAK] and others.).

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Author and article information

Journal

Journal ID (nlm-ta): J Clin Res Pediatr Endocrinol

Journal ID (iso-abbrev): J Clin Res Pediatr Endocrinol

Journal ID (publisher-id): JCRPE

Title: Journal of Clinical Research in Pediatric Endocrinology

Publisher: Galenos Publishing

ISSN (Print): 1308-5727

ISSN (Electronic): 1308-5735

Publication date (Print): September 2012

Publication date (Electronic): 11 September 2012

Volume: 4

Issue: 3

Pages: 121-126

Affiliations

[1 ] Çukurova University Faculty of Medicine, Department of Pediatric Endocrinology, Adana, Turkey

[2 ] Çukurova University Institute of Sciences, Department of Biotechnology, Adana, Turkey

[3 ] Ankara University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey

[4 ] Cumhuriyet University Faculty of Medicine, Department of Endocrinology, Sivas, Turkey

[5 ] Göztepe Educational and Research Hospital, Department of Pediatric Endocrinology, İstanbul, Turkey

[6 ] Osmangazi University Faculty of Medicine, Department of Pediatric Endocrinology, Eskişehir, Turkey

[7 ] İstanbul University Faculty of Medicine, Department of Pediatric Endocrinology, İstanbul, Turkey

[8 ] Yüzüncü Yıl University Faculty of Medicine, Department of Pediatric Endocrinology, Van, Turkey

[9 ] Mersin Children’s Hospital, Department of Pediatric Endocrinology, Mersin, Turkey

[10 ] Diyarbakır Children’s Hospital, Department of Pediatric Endocrinology, Diyarbakır, Turkey

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* Address for Correspondence :growth Phone : +90 322 338 70 83 E-mail : ktopaloglu@ 123456cu.edu.tr

Article

Publisher Item ID: 205

DOI: 10.4274/Jcrpe.725

PMC ID: 3459159

PubMed ID: 22766261

SO-VID: f899eddc-5be7-43b1-808e-2fe25b02d876

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Distribution of Gene Mutations Associated with Familial Normosmic Idiopathic Hypogonadotropic Hypogonadism

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Estudio del peso al nacer

Most cited references 27

TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction.

TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood.

Inactivating KISS1 mutation and hypogonadotropic hypogonadism.

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