It is presently known that MLL2 gene mutation is responsible for approximately 75% of individuals with Kabuki Syndrome. More recently, mutations of the KDM6A gene have been discovered in 9% of individuals who tested negative for MLL2 gene mutation. Interestingly, the functions of KDM6A and MLL2 are related to each other. They function by either adding (in the case of MLL2) an activating methylgroup or removing (in the case of KDM6A) repressive methyl groups to specific amino acids in a protein called Histone H3. The H3 protein can either be modified by repressive (H3K27me3) or active (H3K4me3) methyl groups. Since the MLL2 and KDM6A genes have mutations, the MLL2 is not adding the active methyl-groups or KDM6A is not removing the repressive groups. In essence, although they are doing the opposite activity, the result is the same – repressing (closed chromatin) the open chromatin state of the H3 protein. As a result, the cells in the body that require gene activation through H3 protein, must now do without.
To help families
better understand the basics of the discovery please see Understanding the
Genetics of Kabuki and Epigenetics and How it Relates to Kabuki Syndrome. It is speculated that Kabuki is a heterogeneous
syndrome, meaning that multiple genes could potentially be involved. It is
hoped that with continued analysis, other genes will be discovered.