Genotype /phenotype correlations in infertility

DESCRIPTION (provided by applicant): 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.