Can Kabuki syndrome arise even when KMT2D’s main enzyme still works? A new Icelandic study tackles a question many families and researchers have wondered about: if some people with Kabuki syndrome carry missense changes in KMT2D—not full gene breakages—do those changes still disrupt development, and if so, how?
What the researchers did
The team created a mouse model (a laboratory mouse engineered to carry a human disease–related genetic change) with a patient-derived missense variant in KMT2D.
A missense variant is a single-letter DNA change that swaps one amino acid for another in a protein, rather than deleting or truncating it.
Using CRISPR-Cas9 gene editing, they introduced a specific Kabuki-associated variant (called R5230H) into the mouse Kmt2d gene. This variant sits in a region of the protein called the FYRN domain, known to be a hotspot for Kabuki-related changes.
They then carefully examined:
- Growth and physical traits
- Immune features
- Brain structure and behavior
- Kidney development
- Molecular readouts like gene expression and histone marks
(Histones are proteins that package DNA and help control which genes turn on or off.)
Importantly, they compared this new model to the classic Kabuki mouse model that lacks one working copy of Kmt2d.
A key surprise: the enzyme still works
Biochemical tests showed that this missense variant does not reduce KMT2D protein levels and does not lower its global histone-modifying activity. In other words, the protein’s main enzymatic job—adding chemical marks to histones—appears largely intact.
Yet despite this, the mice still developed many Kabuki-like symptoms.
This figure shows where the Kabuki-associated genetic change is in the KMT2D protein, and what kind of effect it has.
(A) A map of the end of the KMT2D protein (in humans and mice). The Kabuki-related change is marked with a lightning symbol and lies in a region called the FYRN domain.
(B) A close-up showing this spot is conserved across species, meaning it is usually important. The change swaps one protein building block (arginine) for another (histidine).
(C) Computer modeling predicts that the overall shape of the protein does not change.
(D) However, the local electrical charge at this spot does change, which may affect how KMT2D interacts with other proteins during development.
(E–F) Survival data show that most embryos develop normally, but fewer survive around birth, suggesting this variant causes problems late in development rather than early in pregnancy.
Core Kabuki features still appear
The mice showed a striking overlap with well-known Kabuki traits:
- Poor growth and shorter bones
- Distinct craniofacial shape
- Low IgA levels, reflecting immune differences
- Fewer Peyer’s patches (immune structures in the gut)
These findings show that these features do not depend solely on loss of KMT2D’s enzyme activity. Even a subtler missense change can disrupt development.
What didn’t happen: brain differences
Unlike earlier Kabuki mouse models, these mice did not show clear learning or visuospatial memory problems, and their hippocampus (a brain region important for memory) looked normal. Markers of adult neuron formation were also preserved.
This suggests that some cognitive features of Kabuki may be more tightly linked to loss of KMT2D’s catalytic activity, while other physical and immune features are not.
A new and important finding: kidney development
One of the most striking discoveries was unilateral kidney agenesis—about 40% of the mice were born with only one kidney.
This had not been seen in previous Kabuki mouse models, but it mirrors what is reported in a significant number of people with Kabuki syndrome.
This makes the model especially valuable for studying kidney development in Kabuki.
Why this matters for understanding Kabuki syndrome
This study challenges a simple story where Kabuki syndrome is caused only by loss of KMT2D’s enzyme function. Instead, it shows that:
- Missense variants can cause Kabuki features without breaking the enzyme
- KMT2D likely has non-enzymatic roles, such as helping protein complexes assemble or guiding development at critical stages
- Different genetic changes may lead to different clusters of symptoms, even within the same diagnosis
That helps explain why Kabuki syndrome can look so variable from person to person.
What this study doesn’t yet answer
This is still a mouse study, not a direct test in people.
It also doesn’t yet pinpoint which non-enzymatic roles of KMT2D matter most, or why brain effects differ between models. Future work will be needed to see how stable these findings are across generations and how they translate to human development.
Bottom line
Kabuki syndrome can arise even when KMT2D’s main enzymatic function is intact.
Missense variants can disrupt development in subtler—but still powerful—ways, reshaping how we think about the biology behind Kabuki and why its features are so diverse.