Karen P. Usdin, Ph.D.

Senior Investigator

Laboratory of Cell & Molecular Biology


Building NIHBC 08, Room 2A19
8 Center Dr
Bethesda, MD 20892

+1 301 496 2189


Research Topics

The Repeat Expansion Diseases (REDs) are a large group of human genetic disorders that arise from an expansion or increase in the size of a disease-specific tandem repeat tract or microsatellite. The mechanism of expansion is not fully understood. The pathological consequences of expansion for many of these diseases in this group are also still largely unknown. Most are severely life-limiting and have no effective treatment or cure. My lab is interested in the molecular basis of the unusual mutation responsible for these disorders and in the downstream consequences of this mutation. By identifying the pathways involved in disease pathology, we hope to develop rational approaches to treating these disorders and other disorders like them.

We work on several different REDs, including the Fragile X–related disorders (FXDs; aka the FMR1-related disorders) which include fragile X–associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder, Fragile X–associated primary ovarian insufficiency (FXPOI), a disorder involving infertility, menstrual abnormalities and early menopause, and Fragile X Syndrome (FXS), the most common monogenic cause of intellectual disability and autism. FXS is also associated with a folate-sensitive fragile site coincident with the expansion. Fragile sites are prone to breakage in vivo and coincide with deletion or translocation breakpoints in several malignancies. In FXS, fragility leads to the elevated loss of the affected X chromosome. We also study Huntington’s Disease (HD), an autosomal dominant CAG-repeat expansion disorder associated with uncontrollable dance-like movements (chorea), as well as behavioral changes and cognitive decline, Friedreich’s ataxia (FRDA), an early onset autosomal recessive GAA-repeat expansion disorder associated with loss of mobility and hypertrophic cardiomyopathy, and Glutaminase Deficiency Disorder (GLSD), a CAG-repeat expansion disorder, associated with developmental delay, progressive ataxia and refractory seizures. In addition to their relevance to human health, these diseases 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 several different approaches to understanding these diseases including in vitro biochemistry and studies of various patient cell and animal models often using CRISPR technology to make mutations in genes of interest. Our work has demonstrated that the expansion mutation results from the novel interaction of multiple proteins normally involved in DNA mismatch repair (MMR). Interestingly, recent genome-wide association studies have implicated some of these same factors as important modifiers of age at onset and disease severity in a number of REDs. These findings suggest possible drug targets for delaying the age of onset in those diseases like HD where somatic expansion contributes to a high disease burden and early mortality. However, just how these MMR proteins that normally protect the genome against microsatellite instability, end up causing it is unclear. Our current work is aimed at gaining a better understanding of the key steps in this process and identifying good targets for therapeutic intervention.

We are also trying to understand the molecular mechanism responsible for the repeat-mediated epigenetic silencing that is seen in many of these disorders. We have shown that the transcript of the FMR1 gene plays a key role in the FMR1 gene silencing that causes FXS by recruiting the Polycomb Repressive Complex 2 (PRC2). 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. Our recent work has also shown that a subset of heterochromatic modifications associated with the expanded repeat are not involved in gene silencing as we expected. Instead, they act to prevent chromosome fragility and other events likely to threaten genome integrity. We hypothesize that these threats result from the propensity of the FX repeats to form stable blocks to DNA replication, as we demonstrated in vitro many years ago. Transcription would likely exacerbate any problem associated with replication fork progression, raising the possibility that FX gene silencing occurs in response to the resultant increased replication stress.

We are also interested in developing better tools for diagnosis and research. To this end we have recently developed a package of robust, cost-effective, and sensitive diagnostic assays for the FXDs that are suitable for use both in the laboratory and clinic. We are also working with the Undiagnosed Diseases Program at the NIH to identify additional new Repeat Expansion Diseases and to develop assays suitable for diagnosing a variety of newly identified diseases in this group.


  • Scientific Advisory Board of the National Fragile X Foundation
  • Editorial board of NAR Molecular Medicine
  • Co-chair NIH DNA Repair Interest Group

Selected Publications

  1. Hwang YH, Hayward BE, Zafarullah M, Kumar J, Durbin Johnson B, Holmans P, Usdin K, Tassone F. Both cis and trans-acting genetic factors drive somatic instability in female carriers of the FMR1 premutation. Sci Rep. 2022;12(1):10419.
  2. van Kuilenburg ABP, Tarailo-Graovac M, Richmond PA, Drögemöller BI, Pouladi MA, Leen R, Brand-Arzamendi K, Dobritzsch D, Dolzhenko E, Eberle MA, Hayward B, Jones MJ, Karbassi F, Kobor MS, Koster J, Kumari D, Li M, MacIsaac J, McDonald C, Meijer J, Nguyen C, Rajan-Babu IS, Scherer SW, Sim B, Trost B, Tseng LA, Turkenburg M, van Vugt JJFA, Veldink JH, Walia JS, Wang Y, van Weeghel M, Wright GEB, Xu X, Yuen RKC, Zhang J, Ross CJ, Wasserman WW, Geraghty MT, Santra S, Wanders RJA, Wen XY, Waterham HR, Usdin K, van Karnebeek CDM. Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in GLS. N Engl J Med. 2019;380(15):1433-1441.

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This page was last updated on Wednesday, May 1, 2024