Karen P. Usdin, Ph.D.
Laboratory of Cell and Molecular Biology
Building 8A, Room 2A19
8 Center Dr
Bethesda, MD 20814
+1 301 496 2189
The Repeat Expansion Diseases are a large group of human genetic disorders that arise from an expansion in the size of a disease-specific tandem repeat tract or microsatellite. The mechanism of expansion is unknown. The consequences of expansion depend on a combination of the biochemical properties of the repeat, its location within the affected gene, and the normal function of that gene. My group is particularly interested in those diseases where the repeat is located outside of the open reading frame and thus, where the consequences of expansion are not immediately apparent.
My group focuses primarily on the Fragile X–related disorders. These disorders result from expansion of a CGG•CCG-repeat in the 5’ untranslated region of the FMR1 gene. Expansion has different consequences depending on the number of repeats in the expanded allele. Carriers of so-called premutation (PM) alleles, which have 55–200 repeats, are at risk of a neurodegenerative disorder known as Fragile X–associated tremor/ataxia syndrome (FXTAS). This disorder involves, in addition to gait and balance difficulties, cognitive decline, loss of executive function skills, autonomic dysfunction, and dementia. Female carriers are also at risk for Fragile X–associated primary ovarian insufficiency (FXPOI), a disorder involving infertility, menstrual abnormalities, and a risk of early menopause. Female carriers are also at risk of transmission of an FMR1 allele with >200 repeats to their offspring. Such alleles are known as full mutation (FM) alleles and in contrast to PM alleles, which are often hyperexpressed, FM alleles are epigenetically silenced. This results in Fragile X Syndrome (FXS), the most common heritable cause of intellectual disability. In addition to moderate to severe intellectual disability, symptoms of this disorder include autistic behavior, connective tissue abnormalities, digestive difficulties, and occasionally, hyperphagia and obesity. Expansion also results in the appearance of a folate-sensitive fragile site coincident with the expansion. Fragile sites are prone to breakage in vivo, and such sites in other regions of the genome often coincide with deletion or translocation breakpoints in a number of malignancies. In the case of this particular fragile site, fragility may be responsible for the elevated levels of Turner syndrome seen in females who inherit an FM allele.
These diseases are interesting in part because they provide a window into critical processes such as the preservation of genome stability, chromosome structure and epigenetics as well as events that are important for brain and ovarian function.
We are using a number of approaches to look at both the mechanisms of expansion and the consequences of expansion. Our approaches include in vitro biochemistry as well as the use of various stem cell and animal models for different aspects of these diseases. Our recent work has demonstrated that the expansion mutation results from the combined action of proteins normally involved in three different DNA repair pathways, base excision repair, mismatch repair and transcription coupled repair. However, just how these proteins that normally protect the genome against mutation, interact to generate the expansion mutation is unclear. Our current work is aimed at trying to understand this interaction. We are also trying to understand the processes responsible for the repeat-mediated gene dysregulation that is seen in both PM and FM carriers. Amongst our recent findings is the demonstration that the transcript of the FMR1 gene plays a key role in FMR1 gene silencing. The transcript recruits the Polycomb Repressive Complex 2 (PRC2) to the FMR1 gene, likely via the formation of an RNA:DNA hybrid. Furthermore, we have shown that small molecules that interfere with recruitment of PRC2 or that inhibit the enzymatic activity of this complex can prevent gene silencing. Our data suggests that it may be possible to develop gene-specific treatments for the epigenetic abnormality responsible for FXS. We are also interested in developing better tools for diagnosis and research and have recently developed a package of robust, inexpensive and sensitive diagnostic assays that are suitable for use both in the laboratory and clinic.
These disorders currently have no effective treatments or cure. We hope that a better understanding of the causes and consequences of the underlying mutation will lead to effective treatments for these disorders and for other disorders like them.
- Scientific Advisory Board of the National Fragile X Foundation
- Ph.D., University of Cape Town, 1985
Zhou Y, Kumari D, Sciascia N, Usdin K. CGG-repeat dynamics and <i>FMR1</i> gene silencing in fragile X syndrome stem cells and stem cell-derived neurons. Mol Autism. 2016;7:42.
Hayward BE, Zhou Y, Kumari D, Usdin K. A Set of Assays for the Comprehensive Analysis of FMR1 Alleles in the Fragile X-Related Disorders. J Mol Diagn. 2016;18(5):762-774.
Kumari D, Usdin K. Polycomb group complexes are recruited to reactivated FMR1 alleles in Fragile X syndrome in response to FMR1 transcription. Hum Mol Genet. 2014;23(24):6575-83.
Kumari D, Usdin K. Sustained expression of FMR1 mRNA from reactivated fragile X syndrome alleles after treatment with small molecules that prevent trimethylation of H3K27. Hum Mol Genet. 2016;25(17):3689-3698.
Zhao XN, Usdin K. FAN1 protects against repeat expansions in a Fragile X mouse model. DNA Repair (Amst). 2018;69:1-5.
Related Scientific Focus Areas
Genetics and Genomics
Molecular Biology and Biochemistry
This page was last updated on June 25th, 2019