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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Crowley, William F; Balasubramanian, Ravi (2017) MicroRNA-7a2 suppression causes hypogonadotropism and uncovers signaling pathways in gonadotropes. J Clin Invest 127:796-797
Maguire, Caroline A; Song, Yong Bhum; Wu, Min et al. (2017) Tac1 Signaling Is Required for Sexual Maturation and Responsiveness of GnRH Neurons to Kisspeptin in the Male Mouse. Endocrinology 158:2319-2329
Abreu, Ana Paula; Kaiser, Ursula B (2016) Pubertal development and regulation. Lancet Diabetes Endocrinol 4:254-264
Simavli, Serap; Abreu, Ana Paula; Kwaan, Mary R et al. (2016) Candidate gene analysis in a case of congenital absence of the endometrium. Fertil Res Pract 2:3
Stamou, M I; Cox, K H; Crowley Jr, William F (2016) Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the ""-Omics"" Era. Endocr Rev 2016:4-22
Cox, Kimberly H (2016) A Bisphenol by Any Other Name... Endocrinology 157:449-51
Min, Le; Nie, Min; Zhang, Anna et al. (2016) Computational Analysis of Missense Variants of G Protein-Coupled Receptors Involved in the Neuroendocrine Regulation of Reproduction. Neuroendocrinology 103:230-9
Min, Le; Leon, Silvia; Li, Huan et al. (2015) RF9 Acts as a KISS1R Agonist In Vivo and In Vitro. Endocrinology 156:4639-48
Stamou, M I; Cox, K H; Crowley Jr, William F (2015) Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the ""-Omics"" Era. Endocr Rev 36:603-21
Abreu, Ana Paula; Macedo, Delanie B; Brito, Vinicius N et al. (2015) A new pathway in the control of the initiation of puberty: the MKRN3 gene. J Mol Endocrinol 54:R131-9

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