Autosomal Recessive Idiopathic Hypogonadotropic Hypogonadism: Genetic Analysis Excludes Mutations in the Gonadotropin-Releasing Hormone (GnRH) and GnRH Receptor Genes

Abstract

Failure of the normal pattern of episodic secretion of GnRH from the hypothalamus results in the clinical syndrome of idiopathic hypogonadotropic hypogonadism (IHH), with failure of pubertal development and infertility. The only gene that has been implicated in normosmic IHH is the GnRH receptor gene (GNRHR), which accounts for 10% of cases. This report presents four families with autosomal recessive IHH, including a consanguineous pedigree from the Middle East. Defects within the genomic coding sequence of the GNRHR, and the GnRH gene itself, GNRH1, were excluded by temperature gradient gel electrophoresis, direct sequencing, and haplotypes created from simple sequence polymorphisms flanking the GNRH1 and GNRHR loci. We concluded that: 1) genetic analysis has excluded sequence variations in GNRH1 and GNRHR in four families with recessive IHH, suggesting the existence of a novel, as-yet-undiscovered gene for this condition, and 2) because mutation analysis of genomic coding sequence will fail to detect mutations deep within introns or regulatory regions, haplotype analysis is the preferred genetic methodology to eliminate the role of specific candidate genes.

New insights in the genetics of isolated hypogonadotropic hypogonadism

“…The frequency of GnRHR loss-of-function mutations is 50% in familial cases but this frequency drops below 10% in total cases comprising sporadic and familial cases (11). This genetic heterogeneity was confirmed by linkage analysis in informative families (7,12). Thus the presence of other genes encoding for unsuspected or undiscovered proteins playing a major role in the gonadotropic axis was suggested.…”

Kisspeptin and KISS1R: a critical pathway in the reproductive system

“…Along with the reporting of the lossof-function mutations in humans, phenotypic characterization of mice with targeted deletion of Kiss1r was also described (Funes et al 2003, Seminara et al 2003. The Kiss1r knockout mice also displayed hypogonadotropic hypogonadism, demonstrating parallelism to the human disease model.…”

“…The reproductive dimension of the kisspeptin/KISS1R system was revealed in late 2003, when two groups independently reported the presence of deletions and inactivating mutations of KISS1R in patients with idiopathic hypogonadotropic hypogonadism (IHH), a condition characterized by low sex steroids and gonadotropin levels (de Roux et al 2003, Seminara et al 2003. Along with the reporting of the lossof-function mutations in humans, phenotypic characterization of mice with targeted deletion of Kiss1r was also described (Funes et al 2003, Seminara et al 2003.…”

“…In 2001, w40% of probands with autosomal recessive normosmic hypogonadotropic hypogonadism (IHH) and 10-17% of sporadic cases were found to harbor mutations in the GNRHR, the gene encoding the GNRH receptor (Beranova et al 2001, Bo-Abbas et al 2003. Clearly, additional genes were awaiting discovery.…”

“…As briefly described earlier in 2003, groups independently identified KISS1R as a gatekeeper of puberty (de Roux et al 2003, Seminara et al 2003. de Roux et al (2003) recruited a consanguineous family in which five out of eight children had IHH.…”