- Scientific Advisory Board of the National Fragile X Foundation
- Ph.D., University of Cape Town, 1985
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.
- Double-strand break repair plays a role in repeat instability in a fragile X mouse model.
- Gazy I, Hayward B, Potapova S, Zhao X, Usdin K.
- DNA Repair (Amst) (2019 Feb) 74:63-69. Abstract/Full Text
- Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in GLS.
- 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.
- N Engl J Med (2019 Apr 11) 380:1433-1441. Abstract/Full Text
Research in Plain Language
Many human genetic diseases stem from an unusual problem in DNA—specifically the presence of too many copies of a short DNA sequence in one important gene. The Fragile X–related disorders result from too many repeats of the sequence CGG in a gene called FMR1. Fragile X–associated tremor and ataxia syndrome (FXTAS) and Fragile X–associated primary ovarian insufficiency (FXPOI) are seen when the FMR1 gene has 55–200 repeats. FXTAS is a disorder affecting balance and walking. Memory loss, cognitive decline, and other problems are also seen frequently. FXPOI is associated with infertility and an early menopause. Females with 55–200 repeats are also at risk of having a child with Fragile X syndrome. These children have more than 200 repeats in their FMR1 gene. This results in a learning disability that is in fact the most common inherited form of intellectual disability. Affected children also often have autistic symptoms, depression, and behavioral problems.
We are interested in these diseases because they provide a window into critical processes affecting brain and ovarian function, and they affect these organs in ways that scientists do not fully understand yet. We use a number of approaches to look at how these diseases arise and their consequences.