Prevalence, Phenotypic Spectrum, and Modes of Inheritance of Gonadotropin-Releasing Hormone Receptor Mutations in Idiopathic Hypogonadotropic Hypogonadism

Abstract

Mutations in the GnRH receptor (GNRHR) have been described as a cause of reproductive failure in a subset of patients with idiopathic hypogonadotropic hypogonadism (IHH). Given the apparent rarity of these mutations, we set out to determine the frequency and distribution of GNRHR mutations in a heterogeneous population of patients with IHH who were well characterized with respect to diagnosis, phenotype, and mode of inheritance and to define their distribution within the receptor protein. One hundred and eight probands with IHH were screened for mutations in the coding sequence of GNRHR. Forty-eight of the 108 patients had a normal sense of smell, whereas the remaining 60 had anosmia or hyposmia (Kallmann syndrome). Exon segments in the GNRHR were screened for mutations using temperature gradient gel electrophoresis, and all mutations were confirmed by direct sequencing. Five unrelated probands (3 men and 2 women), all normosmic, were documented to have changes in the coding sequence of the GNRHR. Two of these probands were from a subgroup of 5 kindreds consistent with a recessive mode of inheritance, establishing a GNRHR mutation frequency of 2 of 5 (40%) in patients with normosmic, autosomal recessive IHH. The remaining 3 probands with GNRHR mutations were from a subgroup of 18 patients without evidence of familial involvement, indicating a prevalence of 3 of 18 (16.7%) in patients with sporadic IHH and a normal sense of smell. Among the five individuals bearing GNRHR mutations, a broad spectrum of phenotypes was noted, including testicular sizes in the male that varied from prepubertal to the normal adult male range. Three probands had compound heterozygous mutations, and two had homozygous mutations. Of the eight DNA sequence changes identified, four were novel: Thr(32)Ile, Cys(200)Tyr, Leu(266)Arg, and Cys(279)TYR: COS-7 cells transiently transfected with complementary DNAs encoding the human GNRHR containing each of these four novel mutations failed to respond to GnRH agonist stimulation. We conclude that 1) the spectrum of phenotypes in patients with GNRHR mutations is much broader than originally anticipated; 2) the frequency of GNRHR mutations may be more common than previously appreciated in familial cases of normosmic IHH and infrequent in sporadic cases; and 3) functional mutations of the GNRHR are distributed widely throughout the protein.

Adult-onset Idiopathic Hypogonadotropic Hypogonadism due to Isolated Pituitary Gonadotropin Deficiency

“…Whether the HH is a result of hypothalamic or pituitary dysfunction, or both, remains unclear (10). Mutation in the gene encoding the GnRH receptor also shows a wide spectrum of phenotype of HH (11). However, we found no report of a complete blunt response of gonadotropin to repetitive GnRH injection in patients with such gene mutations.…”

Cat-eye Syndrome with Isolated Idiopathic Hypogonadotropic Hypogonadism

“…Despite the genetic heterogeneity, only one gene has been identified for normosmic isolated IHH in humans, the GnRH receptor gene (GNRHR) (8). GNRHR mutations account for only 40% of recessive cases, suggesting that other genes play a role in the pathogenesis of IHH (9). In addition to the GNRHR gene, several responsible genes of IHH such as KAL1, DAX-1, PC1, PROP1 have been reported (10).…”

Clinical and molecular analysis of human reproductive disorders in Brazilian patients

“…An increasing number of point mutations in the GnRHR gene have been described in congenital isolated HH. It currently appears that up to 20% of isolated HH patients may have mutations in this receptor (28,29). The clinical features of patients with GnRHR gene mutations are highly variable, even in the same kindred.…”