Cause of Kabuki

It is presently known that KMT2D (also known as 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 KMT2D gene mutation. Interestingly, the functions of KDM6A and KMT2D are related to each other.  They function by either adding (in the case of KMT2D ) 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 KMT2D and KDM6A genes have mutations, the KMT2D 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 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 SyndromeIt 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.