Cure SMA has awarded a $140,000 research grant to Arthur Burghes, PhD, at The Ohio State University, for his project, “Identification of SMA modifiers and deletion/duplication junctions in the SMA region.”
All individuals with SMA lack the SMN1 gene, but have one or more copies of SMN2, the SMA “backup gene.” In general, those with more SMN2 copies have a less severe form of the disease. However, this can vary, even between siblings with SMA, who sometimes have the same number of SMN2 copies but may have different disease severities.
In this project, Dr. Burghes and his team seek to identify the genes which may be differentially expressed between these sibling pairs, which could account for the differences seen in disease severity. The identification of these genes could allow for DNA testing that can more accurately predict disease severity. Additionally, it helps to identify targets for therapeutic intervention in SMA.
In addition, Dr. Burghes’ project will also investigate SMA carriers who have two copies of SMN1 on a single chromosome, and thus cannot be identified by a standard carrier test. The complex nature of the SMN region can complicate SMA carrier and newborn screening. Understanding more about SMN1 duplication could result in a simple test for the occurrence of this event, which would markedly improve carrier detection.
Meet Dr. Burghes
Who are you?
I am Professor of Molecular & Cellular Biochemistry (also on the staff of the Departments of Neurology and Molecular Genetics) at The Ohio State University. I am also a 1984 graduate of the University of London, where I did my research at The Jerry Lewis Muscle Research Centre under the direction of Dr. Michael Dunn and Professor Victor Dubowitz. The focus of my research as a graduate student in London, and later as a post-doctoral fellow at the Hospital for Sick Children in Toronto was Duchenne muscular dystrophy. I was involved in positional cloning of the gene for DMD while working Dr. Ron Worton’s lab in Toronto, and realized while still a graduate student, that these techniques could be applied to SMA.
How did you first become involved with SMA research?
While working on my graduate research at the Hammersmith Hospital, I had contact with clinicians and attended regular pathology conferences conducted by Prof. Dubowitz, his residents and fellows in pediatrics and neo-natal medicine. It occurred to me that SMA could benefit from the research approaches being developed for DMD. It was not until I started my own lab at OSU in 1988 that I was able to pursue my interest in SMA research. I have never looked back.
What is your current role in SMA research?
Along with the many graduate students, post-docs and research scientists who have passed through my lab (some of whom still work on SMA), I was involved in mapping the gene for SMA as well as characterization of SMN in various ways; created the mouse model of SMA that has been distributed worldwide for use in SMA research; identified chemical compounds and other types of therapies with potential therapeutic benefit. The majority of the professionals who trained in my laboratory are still active in SMA research. I hope that I have inspired their dedication to this worthy cause.
What do you hope to learn from this research project?
The project objective is twofold. The first objection is to identify the genes in humans that cause a milder or no phenotype in siblings despite having the loss of SMN1 and the same copy number of SMN2. The second objective is to identify deletion and duplication junctions so as to improve, in particular, carrier screening.
How will this project work?
We will determine all variants that differ between discordant siblings and concordant siblings. These will then be compared and all variants that differ in concordants will be eliminated from the discordant file. The remaining variants can mark the modifying gene(s) in SMA. Junctions will be identified in both carriers and patients using novel genome sequencing techniques.
What is the significance of your study?
The identification of modifiers of SMA allows accurate DNA testing that can predict phenotype as well as targets for therapeutic intervention in SMA. The identification of junction fragments when two SMN1 genes are present on the same chromosome will aid carrier testing by identifying when this is the case. Deletion junctions may cluster allowing simplification of DNA testing and identification of carriers of this deletion.
Basic Research Funding
This grant to Dr. Burghes is part of $955,000 in new basic research funding that we’re currently announcing.
Basic research is the first step in our comprehensive research model. We fund basic research to investigate the biology and cause of SMA, in order to identify the most effective strategies for drug discovery. We also use this funding to develop tools that facilitate SMA research.