The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism.
OBJECTIVE
To determine the prevalence of GNRH receptor (GNRHR) gene mutations in a large cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH).


METHODS
Molecular analysis and genotype/phenotype correlations.


METHODS
University molecular reproductive endocrinology laboratory.


METHODS
North American and Turkish patients with IHH.


METHODS
DNA from 185 IHH patients were subjected to denaturing gradient gel electrophoresis for exons and splice junctions of the GNRHR gene. Variant fragments were sequenced.


METHODS
GNRHR mutations were characterized and compared with the phenotype. The prevalence of GNRHR mutations was also determined.


RESULTS
Three of 185 (1.6%; confidence interval [CI] 0.3%-4.7%) total IHH patients demonstrated compound heterozygous GNRHR mutations. All three were identified from a cohort of 85 normosmic patients (3.5%, CI 0.73%-7.5%), and none were demonstrated in hyposmic or anosmic IHH patients. GNRHR mutations were identified in 1 of 15 (6.7%; CI 0.2%-32.0%) families with at least two affected siblings, and in 2 of 18 (11.1%; CI 1.4%-34.7%) normosmic females. None were found in presumably autosomal dominant families.


CONCLUSIONS
GNRHR mutations account for approximately 3.5% of all normosmic and 7%-11% of presumed autosomal recessive IHH, suggesting that additional genes play an important role in normal puberty. We believe this to be the largest GNRHR gene mutation analysis performed to date in a population of IHH patients.
Bhagavath
Balasubramanian
B
Division of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia, USA.
Ozata
Metin
M
Ozdemir
I C
IC
Bolu
Erol
E
Bick
David P
DP
Sherins
Richard J
RJ
Layman
Lawrence C
LC
D015331:Cohort Studies; D016001:Confidence Intervals; D005260:Female; D005838:Genotype; D006801:Humans; D007006:Hypogonadism / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D015995:Prevalence; D011966:Receptors, LHRH / Q000235:genetics*
D011966:Receptors, LHRH