The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism

Balasubramanian Bhagavath, Metin Ozata, I. C. Ozdemir, Erol Bolu, David P. Bick, Richard J. Sherins, Lawrence C Layman

Research output: Contribution to journalArticle

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Abstract

Objective: To determine the prevalence of GNRH receptor (GNRHR) gene mutations in a large cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH). Design: Molecular analysis and genotype/phenotype correlations. Setting: University molecular reproductive endocrinology laboratory. Patient(s): North American and Turkish patients with IHH. Intervention(s): 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. Main Outcome Measure(s): GNRHR mutations were characterized and compared with the phenotype. The prevalence of GNRHR mutations was also determined. Result(s): 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. Conclusion(s): 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.

Original languageEnglish (US)
Pages (from-to)951-957
Number of pages7
JournalFertility and Sterility
Volume84
Issue number4
DOIs
StatePublished - Oct 1 2005

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LHRH Receptors
Hypogonadism
Mutation
Confidence Intervals
Genes
Kallmann Syndrome
Denaturing Gradient Gel Electrophoresis
Endocrinology
Genetic Association Studies
Puberty
Idiopathic Hypogonadotropic Hypogonadism
Siblings
Exons
Outcome Assessment (Health Care)
Phenotype
DNA

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology

Cite this

The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism. / Bhagavath, Balasubramanian; Ozata, Metin; Ozdemir, I. C.; Bolu, Erol; Bick, David P.; Sherins, Richard J.; Layman, Lawrence C.

In: Fertility and Sterility, Vol. 84, No. 4, 01.10.2005, p. 951-957.

Research output: Contribution to journalArticle

Bhagavath, Balasubramanian ; Ozata, Metin ; Ozdemir, I. C. ; Bolu, Erol ; Bick, David P. ; Sherins, Richard J. ; Layman, Lawrence C. / The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism. In: Fertility and Sterility. 2005 ; Vol. 84, No. 4. pp. 951-957.
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abstract = "Objective: To determine the prevalence of GNRH receptor (GNRHR) gene mutations in a large cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH). Design: Molecular analysis and genotype/phenotype correlations. Setting: University molecular reproductive endocrinology laboratory. Patient(s): North American and Turkish patients with IHH. Intervention(s): 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. Main Outcome Measure(s): GNRHR mutations were characterized and compared with the phenotype. The prevalence of GNRHR mutations was also determined. Result(s): 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. Conclusion(s): 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.",
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AU - Ozdemir, I. C.

AU - Bolu, Erol

AU - Bick, David P.

AU - Sherins, Richard J.

AU - Layman, Lawrence C

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