Exploring Kabuki Syndrome as a Treatable Cause of Intellectual Disability

One of Johns Hopkins’ NIH award recipient, Bjornsson, is based in the school of medicine’s McKusick-Nathans Institute of Genetic Medicine. His research group studies genetic disorders with epigenetici consequences. These disorders often affect proteins known as histones, which associate with DNAi and can affect whether genesi are turned “off” or “on.” The group’s particular focus is on Kabuki syndrome, which causes intellectual disability, immunological problems and distinctive facial features. Bjornsson is looking for ways to treat the disease by correcting a problem with chemical groups added to the histone tails.

Kabuki syndrome: A deficient highlighter in the book of life

The human body has many different cells yet they all share identical information content. The human genomei (the book of life), which is the encyclopedia of all the machinery in all the cells has about 20000 genes (words). How does a cell decide which genes (words) to use at a specific time? One way is through the use of epigeneticsi. Epigenetic modifications sit close to the genes (words) they affect and thereby essentially highlight (or strikethrough) the genes (words) that should be used by that cell type at that time. 

Kabuki syndrome is a disorder of the epigenetic machinery where one of these highlighters is broken (a histone H3K4 trimethylating enzyme called MLL2).  Since the highlighting function is an ongoing activity in cells it is much more reversible than your typical genetic mutation. By affecting the balance between highlighters and erasers we hope to be able to develop a therapy for the intellectual disability seen in this disease even if patients are diagnosed after the first few years of life when most of the neurons have formed.

Plan. We want to see whether the intellectual disability seen in our patients can be improved after birth. One way of doing this in a very definite manner would be to create a special mouse model that will allow us to titrate the dose of the Mll2 gene (the highlighter affected in Kabuki syndrome) with the drug tetracycline. This would allow us to see whether this disease is a treatable cause of intellectual disability even after birth. This would also allow testing at different ages to determine the most effective timing of treatment. 

How will this help develop therapy for disease. Most people believe that intellectual disability cannot be treated after a critical developmental window. By showing that Kabuki syndrome is a treatable cause of intellectual disability even after birth it will make it feasible to seek therapeutic agents that affect the epigenetic machinery.

A novel mouse model for Kabuki syndrome. Kabuki syndrome is caused by a defect in one of the epigenetic “highlighters” of the book of life. Here we propose making a mouse model where the amount of this “highlighter” can be titrated with the drug tetracycline. This model will help demonstrate that the intellectual disability seen in Kabuki syndrome is treatable even in postnatal life.

Recap. Most people don't believe that you can treat intellectual disability at all, as the general dogma is that intellectual disability is caused by problems early in development that cannot be fixed after birth. However, one can create a mouse model where one copy of a gene (such as MLL2) is repressed but responsive to tetracycline. The benefit here is that one can go through development with only a single working copy but then at a particular timepoint initiate tetracycline to "turn on" the second copy. Then you can ask, can this disorder be treated after birth or has the damage already been done and is irreversible? If one were to demonstrate that Kabuki syndrome is caused by an ongoing biochemical defect rather than a structural insult we think many people would become interested in therapeutic development because then it would less risky for academic investigators (and even drug companies). So this proposal is one step upstream of therapeutic development but we think it is the way to go.

Dr. Bjornsson’s background. Dr. Bjornsson MD. Ph.D. did his graduate work under the supervision of Andrew P. Feinberg, a leader in field of epigenetics. Dr. Bjornsson then joined the combined program in pediatrics and human genetics at Johns Hopkins. During his residency training Dr. Bjornsson worked with Dr. Hal Dietz, a leader in the field of developing therapeutic options for patients with Mendelian disorders. In 2012 Dr. Bjornsson become an assistant professor of pediatrics and genetics at the McKusick-Nathans Institute of Genetic Medicine. He has received multiple awards while at Johns Hopkins both for research and for clinical care. Dr. Bjornsson founded the Epigenetic and Chromatini Clinic in 2012, which is dedicated to the care of patients with epigenetic disorders and disorders of the epigenetic machinery. 

See: National Institute of Health

Donations.  Dr. Bjornsson's lab is the only lab at John Hopkins Hospital dedicated to research on Kabuki syndrome, however it is still very important to specify where you would like your donation to go, otherwise it will end up in the general genetics account.  When donating, please specify Dr. Bjornsson's gift account 80032119 and name (Bjornsson) and then the gift will be linked to the laboratory.  Donations can be made at the Institute of Genetic Medicine.