Determination of Sequence Variation and Haplotype Structure for the Gonadotropin-Releasing Hormone (GnRH) and GnRH Receptor Genes: Investigation of Role in Pubertal Timing

Abstract

Because GnRH and its receptor (GnRHR) are pivotal regulators of the reproductive endocrine axis and mutations in GNRHR lead to hypogonadotropic hypogonadism, we investigated whether genetic variation in GNRHR or GNRH1 affects pubertal timing in the general population. To screen for missense mutations in these genes that might affect pubertal timing, we resequenced the coding regions of these genes in 48 probands with late but otherwise normal pubertal development. No missense variants were found in either gene, except for a previously identified single nucleotide polymorphism (SNP) in GNRH1 that was not associated with late pubertal development. To search for common variants that might affect pubertal timing, we took a haplotype-based association approach. To identify common haplotypes in these genes, we genotyped 41 SNPs in DNA from commercially available European-derived multigenerational pedigrees and participants in a multiethnic cohort (MEC). Two blocks of strong linkage disequilibrium were identified that spanned GNRHR and one was identified spanning GNRH1; within each block, more than 80% of chromosomes carried one of a few common haplotypes. A set of haplotype-tagging SNPs that mark these common haplotypes in all five ethnic groups within the MEC were defined and used to perform association studies among 125 trios (probands with late pubertal development and their parents) and 506 women from the MEC who had early (menarche< 11 yr of age, n = 216) or late (menarche > or = 15 yr of age, n = 290) pubertal development. Three SNPs in GNRHR showed modest association with late pubertal development in the trios; among the 506 women, a different SNP was associated with late menarche, and one rare haplotype was associated with early age of menarche. All of the observed associations were relatively modest and only nominally statistically significant; replication is needed to determine their validity. We conclude that genetic variation in GNRH1 and GNRHR is not likely to be a substantial modulator of pubertal timing in the general population.

Phenotypic variation in constitutional delay of growth and puberty: relationship to specific leptin and leptin receptor gene polymorphisms

“…All subjects demonstrated spontaneous pubertal development. The ethnic distribution of US cases included non-Hispanics (Whites), Cape-Verdian, Hispanics and Asians (13). Height and BMI were measured at the nadir of pubertal delay or in the immediate postpubertal period and SDS were calculated using Centers for Disease Control and Prevention normal ranges (14).…”

Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty

“…CDGP appears to be a multifactorial trait, yet at the same time the inheritance patterns suggests that single genes exert major effects (30). Although previous studies failed to identify mutations in candidate genes in patients with CDGP (33)(34)(35)(36)(37)(38), the GHSR gene has not been previously investigated in patients with this condition (7)(8)(9). We regard our findings as hypothesis generating; it will be of great interest to screen other clinical cohorts with CDGP (as well as family members) to determine the frequency and inheritance pattern of GHSR mutations in various populations.…”

Constitutional delay of growth and puberty is not commonly associated with mutations in the acid labile subunit gene.

“…below mean) and b) severe pubertal delay (R2 S.D. below mean) -lack of breast development in girls R13 years or testicular volume !4 ml in boys O14 years (3,4). Individual growth charts were reviewed to confirm that each child with CDGP demonstrated a slowdown in height gain and subsequent catch up with progression of puberty.…”

“…CDGP is a complex trait with variable degrees of growth retardation and pubertal delay, and is likely to be related to a number of genes (3). Nevertheless, in pedigree analysis of CDGP children, transmission may follow an apparently autosomal dominant pattern with variable penetrance, as well as autosomal recessive and X-linked patterns of inheritance.…”

“…However, no pathogenic gene mutations have been clearly associated with the CDGP phenotype that is characterised by a slowdown in height velocity and tempo of pubertal development. Of the single genes investigated for association with CDGP, polymorphic markers in the genes for GnRH and GnRH-R show only weak association (3). Common polymorphisms in the leptin and leptin receptor genes are not associated with CDGP, although a specific leptin genotype does influence the CDGP phenotype; homozygotes for the long allele for the CT repeat in the 3 0 UTR have a greater body mass index (BMI) SDS than heterozygotes or short allele homozygotes (4).…”