It is presently known that MLL2 genei (also known as KMT2D 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) or removing (in the case of KDM6A) methyl groups to specific
amino acids in a protein called Histone H3.
The H3 protein needs 3 sets of methyl groups to be activated and
therefore work properly. Since the MLL2 and KDM6A genes have mutations,
the MLL2 is adding too many methyl groups and the KDM6A is removing too
many. In essence, although they are doing the opposite activity, the
result is the same – repressing the signal for the H3 protein to do its job. As
a result, the cells in the body that require activation of the H3 protein, must
now do without.
To help families
better understand the basics of the discovery please see Understanding the
Genetics of Kabuki. 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.