PROJECT I (Kl: CROWLEY) The developmental biology of GnRH in humans involves a complex interplay of biochemical and genetic systems all interacting over time and space. Notably, defects in GnRH neuronal ontogeny and function underlie a range of reproductive disorders which account for significant health care expenditures related to its consequent infertility. In the past cycle, strong collaborations between Project I and our Administrative and Phenotyping, Genotyping, and Bioinformatics Cores (Cores A &B), have allowed our Center to assemble a population of >1,300 patients/families with GnRH deficiency. We have successfully used this cohort to identify novel genes affecting the biology of the GnRH neurons and define patient phenotypes. This expanding database;its unique phenotypes and increasing genotypes;our global network of referring physicians and our increasing bioinformatic infrastructure provides a unique 'platform for human gene discovery'that will permit us to use state-of-the art genetic and genomic tools to augment the power, speed, and resolution of our gene discovery program.
In Specific Aim 1, we will use contemporary genetic and genomic tools including endogamous populations; copy number variations and methylation pattern analysis;and whole exomic sequencing to identify novel genes underlying human isolated GnRH deficiency.
Specific Aim 1 will also map the oligogenic interactions between the genes in the pathogenesis of isolated GnRH deficiency in humans.
In Specific Aim 2, we will characterize the full genotypic-phenotypic spectrum of these new genes in the human and use the identified mutated regions of the genes to define their domain-specific biologic interactions. Finally, in Specific Aim 3, we will define the rotes played by these new genes causing isolated GnRH deficiency in common reproductive disorders such as hypothalamic amenorrhea (HA), delayed and precocious puberty.

Public Health Relevance

This project aims to identify the genes which control puberty and reproduction in the human. By gaining a better understanding of the genetic basis of reproductive disorders we can begin to develop better diagnostic approaches, new treatment, and better counsel patients and families with these conditions.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1-DSR-L)
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Massachusetts General Hospital
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Macedo, Delanie B; Abreu, Ana Paula; Reis, Ana Claudia S et al. (2014) Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. J Clin Endocrinol Metab 99:E1097-103
Beneduzzi, Daiane; Trarbach, Ericka B; Min, Le et al. (2014) Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay. Fertil Steril 102:838-846.e2

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