Although infertility affects 10-15% of all individuals attempting to have children, little is known about the molecular basis of human puberty and fertility. The long-term goal of this laboratory is to elucidate the mechanisms underlying the development of normal puberty and reproductive capability by utilizing patients with infertility who possess gene mutations. The applicant will study two groups of infertile patients: those with idiopathic hypogonadotropic hypogonadism (LHH) and those with normal puberty who have ovulation disorders or sperm abnormalities. Patients with IHH constitute a severe reproductive-deficient phenotype with absent puberty, low serum gonadotropins, and infertility. Most infertility patients have normal puberty, and constitute men with sperm abnormalities (azoospermia, oligospermia. and/or asthenospermia) or women with ovulation disorders. The applicant?s overlying hypothesis is that identification of the genetic mutations in these groups will lead to a better understanding of: 1) which forms of IHH are hereditary; 2) whether FSH is necessary for normal sperm concentration and fertility in men, follicular development beyond the antral stage in women, and for normal androgens in both men and women; and 3) whether gene mutations affect the function of the encoded proteins. These hypotheses will be addressed by the following specific aims:
Specific Aim 1 : To test candidate genes for linkage and/or mutations in IHH patients;
Specific Aim 2 : To screen infertility patients for FSH beta mutations, specifically those with abnormal semen analyses and those with ovulation disorders, likely to possess FSH-beta mutations;
Specific Aim 3 : To create the mutants, express them in vitro, and determine their effects upon the encoded protein. The elucidation and analysis of gene mutations in infertile patients will be important to determine the genetic basis of some forms of infertility and to determine the underlying mechanisms of puberty and reproduction.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HD040287-05
Application #
7114939
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Parrott, Estella C
Project Start
2002-08-14
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2008-07-31
Support Year
5
Fiscal Year
2006
Total Cost
$151,012
Indirect Cost
Name
Georgia Health Sciences University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Xu, Ning; Kim, Hyung-Goo; Bhagavath, Balasubramanian et al. (2011) Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome. Fertil Steril 95:1613-20.e1-7
Xu, Ning; Bhagavath, Balasubramanian; Kim, Hyung-Goo et al. (2010) NELF is a nuclear protein involved in hypothalamic GnRH neuronal migration. Mol Cell Endocrinol 319:47-55
Kim, Hyung-Goo; Ahn, Jang-Won; Kurth, Ingo et al. (2010) WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet 87:465-79
Kim, Hyung-Goo; Pedersen-White, Jennifer; Bhagavath, Balasubramanian et al. (2010) Genotype and phenotype of patients with gonadotropin-releasing hormone receptor mutations. Front Horm Res 39:94-110
Layman, Lawrence C; Tho, Sandra P T; Clark, Andrew D et al. (2009) Phenotypic spectrum of 45,X/46,XY males with a ring Y chromosome and bilaterally descended testes. Fertil Steril 91:791-7
Kim, Hyung-Goo; Bhagavath, Balasubramanian; Layman, Lawrence C (2008) Clinical manifestations of impaired GnRH neuron development and function. Neurosignals 16:165-82
Pedersen-White, Jennifer R; Chorich, Lynn P; Bick, David P et al. (2008) The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Mol Hum Reprod 14:367-70
Kim, Hyung-Goo; Kurth, Ingo; Lan, Fei et al. (2008) Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet 83:511-9
Bhagavath, Balasubramanian; Xu, Ning; Ozata, Metin et al. (2007) KAL1 mutations are not a common cause of idiopathic hypogonadotrophic hypogonadism in humans. Mol Hum Reprod 13:165-70
Bhagavath, Balasubramanian; Layman, Lawrence C (2007) The genetics of hypogonadotropic hypogonadism. Semin Reprod Med 25:272-86

Showing the most recent 10 out of 18 publications