Research Update and New Directions, AHC Gene Project 2002

February 2002 by Dr. Kathryn Swoboda We would like to take this opportunity to update you regarding a number of exciting developments in the AHC gene project. The work on finding the gene or genes causing AHC has greatly expanded in the past year with the transition from Dr. Ptacek’s laboratory to a completely independent laboratory effort focused primarily on AHC. This effort remains under the direction of Dr. Swoboda, but brings together a number of collaborative groups at the University of Utah, Eccles Institute of Human Genetics as well as laboratories elsewhere in the U.S. and internationally to expand the effort to uncover the genetic cause of AHC. We have added a number of new team members to the laboratory this year who are an integral part of this effort. A brief summary of the special attributes they bring to the project and their primary roles are listed below. These include Mylynda Schlesinger, Justine Milligan, Josh Magleby, Victoria McMeen and Luke Miller. Mylynda Schlesinger Ph.D. is a medical student who recently received her doctoral degree in Biochemistry and Molecular Genetics at the University of Utah. She has played a critical role in expanding and analyzing the collection of important clinical data necessary to direct our work. She brings complementary expertise and experience in techniques integral to our effort in the laboratory effort as well, including our current cell culture and RNA work. We expect that she will be a longstanding champion and partner in the AHC gene project. Justine Milligan is a laboratory specialist with extensive expertise in techniques involving the identification of genes and genetic mechanisms causing disease. She was recruited from a molecular biotech company in Boston, and gained much of her experience in research efforts at the Brigham and Women’s Hospital and Dana Farber Cancer Institute. Her time and focus is primarily dedicated to finding the gene or genes causing AHC, and her dedication and expertise has improved the efficiency and productivity in evaluating candidate genes which are potentially implicated in the cause of this disorder. Over the past few months she has performed extensive evaluation of genes at the translocation breakpoint in the family with AHC and a chromosome abnormality, as well as evaluation of other “candidate genes” including brain expressed calcium channel genes. She is helping with our current linkage analysis effort, a complimentary approach to try to identify other regions in the genome (all the DNA found in a cell in that individual that makes up the chromosomes) that might have a role in causing the disorder. Victoria McMeen is a clinical research coordinator working with us on this project. She assumed Catherine McKenna’s position after Catherine moved to Denver several months ago. She brings special expertise, passion and dedication to the AHC effort with her nursing and medical school training in pediatrics in the Ukraine. She has proved extremely helpful in obtaining and organizing data in a timely fashion to complement our laboratory effort, grant funding efforts and plays a critical role in helping with our documentation and institutional review board requirements. She also helps with tissue culture and processing of DNA samples, and plays a critical role in maintaining and updating our computerized clinical database. Josh Magleby is a graduate student pursuing his Ph.D. in psychology at the University of Utah. He and his advisor, Janiece Pompa, Ph.D., have agreed to spearhead the effort in a neuropsychological study of AHC patients. He and Mylynda Schlesinger have been working with one of our Utah AHC patients, Carly, to refine techniques which can be used to help clarify some of the specific strengths and learning problems our children with AHC face as they and their families cope with the sometimes unpredictable course of this illness. One targeted goal of this research will be to create specific guidelines for families and teachers about the ideal environment and strategies for maximizing outcome in terms of developmental abilities and skills in children with AHC. Luke Miller is an undergraduate student with an interest in the biomedical sciences. He volunteers his time to help us with any number of tasks, making him an important asset to our efforts. This includes packing FEDEX kits, helping maintain our literature database, stocking supplies, helping with paperwork, and numerous other tasks that make our effort run more smoothly and efficiently. Adam Craner, F.N.P. is a nurse practitioner working with Dr. Swoboda at Primary Children’s Medical Center. He recently accompanied Dr. Swoboda and Justine Milligan to France, where they had they opportunity to meet 22 patients and families with AHC. His expertise in performing electrocardiograms, skin biopsies and blood draws was invaluable, and allowed Dr. Swoboda to focus on obtaining critical clinical information from the patients and families. His delight in interacting with and working with children, and his compassion and caring in his interactions with the families make him a special addition to the team. In addition to the above laboratory and clinical team members, we have begun several collaborations with laboratories at the University of Utah and elsewhere to help speed our efforts, and make them more efficient. A few of these are outlined below, with a brief update regarding current status. Candidate gene analysis: A gene which, when disrupted in any way, is considered to be a possible primary cause of AHC is considered a “candidate gene”. Candidate genes for AHC are many, and include 1) genes that might be disrupted by the chromosome breakage in the family with AHC and a chromosome translocation – of course this has already been the source of extensive work in the laboratory, which is ongoing. 2) calcium channel genes – this hypothesis has been appealing for two reasons; a) flunarizine is the only medication to date that has any evidence showing benefit in at least a subset of AHC patients, and its predominant function is as a calcium channel blocker b) familial hemiplegic migraine, a neurologic disorder which shares many similarities to AHC has been found in some cases to be due to disruption of a calcium channel gene. 3) Other ion channel and receptor genes which play a role in initiating, maintaining or diminishing the electrical activity in certain cells in the brain – these are numerous. As we continue to work on the chromosome breakage issue, and pursue other studies to help narrow down our region of focus to find the gene or genes involved, we have obtained the help of the High Throughput Sequencing Laboratory at the University of Utah, under the direction of Robert Weiss, Ph.D. His laboratory has played an integral role in providing rapidly acquired high throughput DNA sequence for the international human and mouse genome sequencing projects. With his laboratory’s expertise, we are able to analyze calcium channel genes, which are typically very large, at a fraction of the time and cost it would otherwise entail. This would be much more difficult and time-consuming to do on our own, and we are incredibly grateful for their expertise and willingness to assist us in our efforts. In a new effort to identify other mechanisms operative in AHC, and to expand our effort to uncover the biochemical basis of the disorder, we have decided to obtain skin biopsies in some patients. Skin cells can grow and reproduce in culture, and are widely used to measure a number of critical processes that occur in cells, including some aspects of energy metabolism. They can be easily sent from laboratory to laboratory. We are currently growing up skin cells from a number of patients we visited recently in France, and will use protein and RNA (ribonucleic acid, which is made from DNA in cells) to do microarray studies in collaboration with James Metherall Ph.D. These microarray studies will allow us to look downstream at what is being expressed in the cells of patients, and see if we can detect differences compared to children without AHC. This utilizes a new technology which allows us to look at hundreds of different products at once, and to try to pick out differences which might lead us in a new direction.