Abstract

Project 2 Genetic analysis of rare, severe Mendelian reproductive conditions has highlighted the critical importance of GnRH neurons in pathophysiology. To further elucidate these biological processes, we will extend the genetic investigations to analyses of common variation on the following common reproductive clinical disorders: polycystic ovarian syndrome (PCOS), primary ovarian insufficiency (POI), and hypothalamic amenorrhea (HA). Specifically, we will 1) accelerate the discovery of novel genetic influences on reproductive phenotypes through large-scale international consortia; 2) integrate these new genetic discoveries with the Mendelian analyses of P1 to nominate genes and variants for P3; and 3) synthesize the genetic results across complex reproductive traits to understand how they relate as well as characterizing the phenotypic and biological consequences of validated genes and variants from zebrafish P3 through deep phenotyping. If successful, we will uncover new genes and variants for reproductive clinical endpoints, provide these for functional validation and then interpret the full range of phenotypic consequences of these genetic influences.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center (P50)
Project #
5P50HD028138-30
Application #
9910433
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
30
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114

  Publications

Stamou, M I; Plummer, L; Galli-Tsinopoulou, A et al. (2018) Unilateral renal agenesis as an early marker for genetic screening in Kallmann syndrome. Hormones (Athens) :
Lippincott, Margaret F; Nguyen, Kiana; Delaney, Angela et al. (2018) Assessing Sex Steroid Influence on Kisspeptin Responsiveness in Idiopathic Hypogonadotropic Hypogonadism. J Endocr Soc 2:1293-1305
Guo, Michael H; Plummer, Lacey; Chan, Yee-Ming et al. (2018) Burden Testing of Rare Variants Identified through Exome Sequencing via Publicly Available Control Data. Am J Hum Genet 103:522-534
Terasawa, Ei; Garcia, James P; Seminara, Stephanie B et al. (2018) Role of Kisspeptin and Neurokinin B in Puberty in Female Non-Human Primates. Front Endocrinol (Lausanne) 9:148
Garcia, James P; Keen, Kim L; Kenealy, Brian P et al. (2018) Role of Kisspeptin and Neurokinin B Signaling in Male Rhesus Monkey Puberty. Endocrinology 159:3048-3060
Shahab, Muhammad; Lippincott, Margaret; Chan, Yee-Ming et al. (2018) Discordance in the Dependence on Kisspeptin Signaling in Mini Puberty vs Adolescent Puberty: Human Genetic Evidence. J Clin Endocrinol Metab 103:1273-1276
Chan, Yee-Ming; Lippincott, Margaret F; Kusa, Temitope O et al. (2018) Divergent responses to kisspeptin in children with delayed puberty. JCI Insight 3:
Stamou, Maria I; Georgopoulos, Neoklis A (2018) Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism. Metabolism 86:124-134
Cox, Kimberly H; Oliveira, Luciana M B; Plummer, Lacey et al. (2018) Modeling mutant/wild-type interactions to ascertain pathogenicity of PROKR2 missense variants in patients with isolated GnRH deficiency. Hum Mol Genet 27:338-350
Teive, Hélio Afonso Ghizoni; Camargo, Carlos Henrique F; Sato, Mario Teruo et al. (2018) Different Cerebellar Ataxia Phenotypes Associated with Mutations of the PNPLA6 Gene in Brazilian Patients with Recessive Ataxias. Cerebellum 17:380-385

Showing the most recent 10 out of 41 publications