The goals of our Center, Modifiers of FRM1-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 FRM1-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.
The aims of the Administrative Core are to: 1) provide leadership and a center structure within which investigators can integrate their ideas, expertise and results, 2) facilitate communication and reporting of results to the scientific community, 3) facilitate research tasks by providing guidance in regulatory processes, budgeting, ordering and preparation of manuscripts and presentations, 4) facilitate data and resource sharing, and 5) provide coordinated research opportunities for students and postdoctoral fellows to engage them in fragile X-related conditions.
The identification of genes whose variation modifies the phenotype of a Mendelian disorder is emerging at the forefront of contemporary human genetics. Characterizing those modifying genes for fragile X syndrome-associated epilepsy, fragile X-associated ovarian insufficiency and fragile X-associated tremor/ataxia syndrome will increase the understanding of perturbed pathways involved in these disorders.
|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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