Distribution of Gene Mutations Associated with Familial Normosmic Idiopathic Hypogonadotropic Hypogonadism

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.

Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay

“…Nevertheless, the possibility of a more remote common ancestry cannot be totally discarded. The p.R139H has also been reported in five other unrelated cases of different geographic origins worldwide, which were not evaluated here, and further studies would be necessary to determine if they too have a common ancestor (12, 30, 44, 47, 48). On the other hand, another mutation affecting the same codon (p.R139C) was described in two cases, raising the possibility that this may be a hotspot region (48, 49).…”

Complete Idiopathic Hypogonadotropic Hypogonadism due to Homozygous <b><i>GNRH1</i></b> Mutations in the Mutational Hot Spots in the Region Encoding the Decapeptide

“…Large-scale screening indicates that GNRHR mutations account for 3.5-16% of sporadic cases of nIHH and up to 40% of familial cases of nIHH [15]. In our cohort, Gurbuz et al [16] previously identified GNRHR gene mutations in 7 of 22 families (31.8%) with nIHH. Mutations in GNRH1 are extremely rare.…”

“…Chan [4] estimated the prevalence of GNRH1 mutations at 0.33% based on 600 pedigrees collectively screened by various groups. Although it has been repeatedly observed that mutations are less frequent in the genes encoding the ligands than in their corresponding cognate receptor [4,16], still, contrasting frequency of GNRH1 and GNRHR mutations has been found to be striking. Nevertheless, it should also be noted that the length of the coding sequences of the ligands are usually much shorter than their cognate receptors, making it less likely to suffer from mutations, as in GNRH1/GNRHR pair.…”

Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

“…The study of IGD in multiplex families from geographically delineated populations with high rates of endogamy has been another highly fruitful method of IGD gene discovery (69). The gene coding for kisspeptin receptor 1 (KISS1R) was discovered using linkage analysis in an endogamous pedigrees with multiple affected Bedouin family members displaying nIHH (70,71).…”