The image maps how a single amino acid swap—arginine to histidine at position 5230 in the FYRN domain—creates a protein that looks intact but behaves differently. At the molecular level, we see the altered chemistry: where arginine carried a strong positive charge, histidine brings a more neutral electrical signature, flipping the magnetic landscape of this evolutionarily conserved pocket without disturbing the protein’s three-dimensional fold. The structural predictions confirm this paradox—the machine keeps its shape, but changes its charge field.

This subtle alteration, drawn from a real patient with relatively preserved cognitive ability, proves sufficient to disrupt development catastrophically. The inheritance charts reveal the biological cost: embryos carrying two copies of this variant die before birth, while single-copy survivors face perinatal vulnerability and a striking 43 percent rate of missing kidneys—a phenotype never seen in models where the protein is simply deleted. The data suggest that during the crucial window when organs are forming, KMT2D operates not merely as an enzyme attaching chemical tags to DNA, but as a structural scaffold whose precise electrostatic properties guide tissue assembly. For parents, this visualizes why some children present with primarily physical differences while others face cognitive challenges—the same gene can fail in different modes, and therapies may need to target these distinct functions separately.

A new mouse model for Kabuki Syndrome, created using a specific genetic change found in a patient, reveals that some core symptoms may arise independently of the enzyme activity typically lost in the condition. This model, which carries a "missense" variant—a single-letter change in the DNA code—recapitulates many physical features of the syndrome but intriguingly spares the brain from certain neurological deficits seen in earlier models.
For over a decade, research into potential therapies has relied primarily on a single mouse model designed to mimic the "loss-of-function" mechanism seen in most Kabuki cases, where one copy of the KMT2D gene is completely disabled. However, an estimated 15–30% of individuals with Kabuki Syndrome have missense variants, where the gene's protein product is made but may be subtly altered. The new study aimed to see if this different type of mutation leads to similar outcomes in a living organism.
Researchers used CRISPR-Cas9 gene-editing to introduce a patient-derived missense variant, known as R5230H, into mice. This variant alters a single building block (an amino acid) within a crucial region of the KMT2D protein called the FYRN domain, a known hotspot for Kabuki-causing missense changes. Computational models suggested this change wouldn't destabilize the protein or cripple its enzymatic function, a prediction borne out in the lab.
The resulting mice, carrying one copy of the R5230H variant, displayed a striking overlap with the older loss-of-function model. They showed significant growth deficiency, distinct craniofacial anomalies, low levels of immunoglobulin A (IgA), and fewer immune structures in the gut called Peyer's patches. This confirms these core Kabuki phenotypes are not an artifact of the older model's engineering and can arise from different genetic mechanisms.
Notably, the new model also exhibited severe challenges not previously emphasized in mice: high rates of death around birth and, in many cases, the complete absence of one kidney (unilateral renal agenesis). Kidney problems affect a significant portion of people with Kabuki Syndrome, making this a clinically relevant new feature for researchers to study.
The most significant divergence from the prior model was in the brain. The R5230H mice did not show the visuospatial memory deficits, reduced hippocampal volume, or impaired adult neurogenesis (the birth of new neurons) that were hallmarks of the loss-of-function model. Correspondingly, global levels of histone methylation—the chemical tags placed by the KMT2D enzyme—remained normal.
This suggests the R5230H variant impairs a function of KMT2D separate from its catalytic, histone-modifying role. The preserved enzyme activity may be why certain neurological disruptions are absent. Intriguingly, the patient who provided this variant had a relatively higher cognitive ability and no reported visuospatial defects, aligning with the mouse findings.
The authors propose this new model is a vital tool.It will help unravel how different KMT2D mutations cause disease and test whether emerging therapies, particularly those that rescued neurological issues in the older model, will be effective across the spectrum of Kabuki Syndrome variants.
**Other findings...
* The study's computational work predicted the amino acid change alters the local electrostatic charge and may disrupt how KMT2D interacts with partner proteins like NCOA6, potentially affecting how the protein complex is recruited within the cell.
* In mice with only one kidney, the remaining organ showed enlarged glomeruli, the kidney's filtering units.
* The authors note that using only female mice in behavioral tests could have influenced the neurological results if sex differences exist.
* A prior, different missense mouse model behaved like a partial-loss variant and only showed symptoms when both gene copies were mutated, unlike the human condition.
generated Feb 25, 2026, 6:25 PM by deepseek-chat (openai-chat-completions api, llm id 4)  Feb 25, 2026, 1:25 PM