GENETICS OF DELAYED PUBERTY

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from the Investigator's Abstract): Idiopathic
hypogonadotropic hypogonadism (IHH) is due to a deficiency of GnRH. The
major goal of this proposal is to isolate the gene(s) important in the
genesis of IHH. In the hypogonadal mouse, hypogonadotropic hypogonadism is
due to a GnRH gene deletion, but no GnRH gene mutations have been identified
in humans with IHH. Except for two X-linked disorders, Kallmann's syndrome,
consisting of IHH and anosmia (KAL mutations) and hypogonadotropic
hypogonadism associated with congenital adrenal hyperplasia (DAX-1 gene
mutations), the etiology of IHH remains unknown. This project will attempt
to identify affected individuals with IHH and to isolate candidate genes
utilizing new approaches. The first specific aim will be to increase the
number of IHH families in the database. The second aim will be to better
characterize the phenotype of IHH patients based upon physical exam,
endocrinologic studies, and pedigree structure. The third aim will be to
use linkage analysis, linkage disequilibrium analysis, and association to
identify candidate genes which might be involved in the pathogenesis of IHH.
The identification of new genes is important for control of reproduction has
tremendous implications for the treatment of pubertal disorders,
infertility, and potentially contraception. Depending upon the types of
mutations characterized, molecular diagnosis might be possible for children
with delayed puberty.

Female and male humans with idiopathic hypogonadotropic hypogonadism (IHH)
typically present with delayed puberty, low serum gonadotropins, and the
absence of pituitary dysfunction and tumor. Current endocrinologic evidence
suggests that IHH is due to a deficiency of gonadotropin releasing hormone
(GnRH), although heterogeneity exists in clinical, endocrinologic, and
genetic attributes of the disorder. The hypogonadal mouse has
hypogonadotropic hypogonadism due to a GnRH gene deletion, but no GnRH gene
mutations have been identified in humans with IHH. Except for two X-linked
disorders, Kallmann syndrome, consisting of IHH and anosmia (KAL gene
mutations), and hypogonadotropic hypogonadism associated with congenital
adrenal hypoplasia (DAX-1 gene mutations), the etiology of IHH remains
unknown. The major goal of this proposal is to isolate genes important in
the genesis of IHH. Our specific aims are: (1) To increase our number of
IHH families; (2) to better characterize the phenotype of IHH patients based
upon physical exam, endocrinologic studies, and pedigree structure; and (3)
to use linkage, linkage disequilibrium, and association to test candidate
genes which might be involved in the pathogenesis of IHH. Despite genetic
heterogeneity, these genetic analyses provide important information for gene
mapping. Although IHH is not a common disorder, it has certain important
characteristics which make the understanding of its pathophysiology
important since it affects puberty and reproduction in both sexes. The
identification of new genes important in reproduction has tremendous
implications for treatment of pubertal disorders, infertility, and
potentially contraception. If a new gene is identified, a better
understanding of IHH, and perhaps more importantly, normal reproduction,
will be gained. Depending upon the types of mutations characterized,
molecular diagnosis might be possible for children with delayed puberty.
New therapies for the treatment of delayed puberty and infertility might
also be possible once the protein structure and function are better
understood. Potentially, contraceptive technologies could be developed
based upon the understanding of the function of newly identified genes.
StatusFinished
Effective start/end date7/1/973/31/16

ASJC

  • Medicine(all)