U.S. Department of Health and Human Services
Karen Usdin

 Contact Info

Tel: 301-496-2189
Email: karenu@helix.nih.gov

 Select Experience

  • Ph.D.University of Cape Town1985

 Related Links

  • Chromosome Biology/Epigenetics
  • Genetics/Genomics
  • Molecular Biology/Biochemistry
  • Stem Cells/Induced Pluripotent Stem Cells
Research Summary/In Plain Language

Research Summary

Research Goal

The Fragile X-related disorders are caused by an unusual mutation that causes disease pathology in ways that are poorly understood. These disorders have no current effective treatment or cure. We hope that a better understanding of the causes and consequences of this mutation will lead to effective treatments for these disorders.

Current Research

The Repeat Expansion Diseases are a large group of human genetic disorders that arise from an increase (expansion) in the number of repeats in a single tandem repeat tract. 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.

The Fragile X–related 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 and 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, 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 not only because they provide a window into critical processes such as brain and ovarian development, but also because there is evidence to suggest that some aspects of disease pathology may involve a variety of interesting and incompletely understood mechanisms such as RNA toxicity and repeat-mediated chromatin remodeling. We are using a number of approaches to look at both the mechanisms of expansion and the consequences of expansion in the Fragile X-related disorders. Our approaches include biochemical studies of the unusual nucleic acid structures formed by disease associated repeats, in situ hybridization and immunocytochemistry to examine the molecular basis of the chromosome fragility seen in individuals with Fragile X syndrome, chromatin immunoprecipitation and qRT-PCR to understand the gene misregulation responsible for both groups of disorders, as well as the development of various in vitro, bacterial, induced pluripotent stem cells (iPSCs), and animal models for different aspects of these diseases.

Applying our Research

These disorders are among the most common heritable disorders affecting learning and memory, gait and balance, and fertility. A better understanding of these disorders may not only be useful for developing treatments for these disorders, but may also be useful for treating other human genetic disorders that have similar underlying mechanisms.

Need for Further Study

These disorders do not currently have an effective treatment or cure. The mechanisms responsible are not fully understood.