The goals of our Center, Modifiers of FMR1-associated disorders: application of high throughput technologies, are targeted to the RFA research area to Advance the understanding of the pathophysiology of FMR1 Related Conditions. The completion of the proposed aims from the three research projects will lead to the identification of the genetic basis of variable expressivity or incomplete penetrance of FMR1-associated conditions. Project A will focus on the variable expression of epilepsy among boys with fragile X syndrome (FXS), a co-morbid condition that occurs among 15% of affected boys and we speculate that variation elsewhere in the genome is responsible. Likewise, Project B will focus on the incomplete penetrance of fragile X tremor/ataxia syndrome (FXTAS) in men, a neurodegenerative disorder among those with the premutation (PM), with a lifetime prevalence of 30% among males. Project C focuses fragile X association primary ovarian insufficiency (FXPOl) which manifests in 20% of PM carriers as premature ovarian failure (POF), or cessation of menses prior to age 40. POF leads to infertility and estrogen-deficiency related disorders usually reserved for the aged. Our goal is to identify and understand the extent of the epistatic effects of modifying genes on these three Mendelian disorders. The Center will include three projects and two shared cores, all administered by an Administrative Core. Each proposed research project will take the same novel approach to define a set of candidate genes for further study in mammalian systems. They will: 1) use the Recruitment Core B to ascertain the 100 cases and 100 controls drawn from extreme phenotypic tails of each disorder, 2) conduct whole genome sequencing on each of the 100/100 cases/controls series using the expertise and experience of the Genomics and Analytical Core C, and 3) after validating variants, assess the function of prioritized genes using the established phenotypic assays in the corresponding Drosophila models. This core will provide a common computational and analytical infrastructure for all projects, leading to natural economies and synergies including: 1) decreased costs due to larger sample sizes per experiment, 2) common equipment use, 3) increased quality control because all experiments use the same protocol, and 4) reduced errors in interpretation of results because of common analytical approaches. This final resource of 600 sequenced genomes of those with FMRI mutations will be available for future analyses by those in scientific community.

Public Health Relevance

The goal of this Genomics and Analytical Core (Core C) within the larger center is to provide the necessary experimental, computational and analytical infrastructure to obtain whole genome sequencing data on 600 samples, map that data to the human genome, find variants, validate those variants for further study, and perform statistical analysis of that data to test for association of variants or loci with phenotypes. The results generated by this core will be fundamental to all goals of this center grant.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54NS091859-03
Application #
9069626
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Bienkowski, Rick S; Banerjee, Ayan; Rounds, J Christopher et al. (2017) The Conserved, Disease-Associated RNA Binding Protein dNab2 Interacts with the Fragile X Protein Ortholog in Drosophila Neurons. Cell Rep 20:1372-1384
Albizua, Igor; Rambo-Martin, Benjamin L; Allen, Emily G et al. (2017) Women who carry a fragile X premutation are biologically older than noncarriers as measured by telomere length. Am J Med Genet A 173:2985-2994
Li, Liping; Zang, Liqun; Zhang, Feiran et al. (2017) Fat mass and obesity-associated (FTO) protein regulates adult neurogenesis. Hum Mol Genet 26:2398-2411
Anderson, Bart R; Chopra, Pankaj; Suhl, Joshua A et al. (2016) Identification of consensus binding sites clarifies FMRP binding determinants. Nucleic Acids Res 44:6649-59
Espinel, Whitney; Charen, Krista; Huddleston, Lillie et al. (2016) Improving Health Education for Women Who Carry an FMR1 Premutation. J Genet Couns 25:228-38
Xie, Nina; Gong, He; Suhl, Joshua A et al. (2016) Reactivation of FMR1 by CRISPR/Cas9-Mediated Deletion of the Expanded CGG-Repeat of the Fragile X Chromosome. PLoS One 11:e0165499
Hipp, Heather S; Charen, Krista H; Spencer, Jessica B et al. (2016) Reproductive and gynecologic care of women with fragile X primary ovarian insufficiency (FXPOI). Menopause 23:993-9
Visootsak, Jeannie; Huddleston, Lillie; Buterbaugh, Allison et al. (2016) Influence of CHDs on psycho-social and neurodevelopmental outcomes in children with Down syndrome. Cardiol Young 26:250-6
Johnston, Henry Richard; Hu, Yijuan; Cutler, David J (2015) Population genetics identifies challenges in analyzing rare variants. Genet Epidemiol 39:145-8
Suhl, Joshua A; Muddashetty, Ravi S; Anderson, Bart R et al. (2015) A 3' untranslated region variant in FMR1 eliminates neuronal activity-dependent translation of FMRP by disrupting binding of the RNA-binding protein HuR. Proc Natl Acad Sci U S A 112:E6553-61

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