A patient-derived missense mouse model of Kabuki syndrome 1
4 affiliations
- 1The Louma G. Laboratory of Epigenetic Research, Faculty of Medicine, University of Iceland, Reykjavik 102, Iceland
- 2Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik 101, Iceland
- 3McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- 4Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21205, USA
Abstract
Kabuki syndrome type 1 (KS1) is a rare cause of intellectual disability resulting from heterozygous pathogenic variants in the gene encoding the histone methyltransferase KMT2D. A previously established loss-of-function mouse model of KS1 exhibits key phenotypic features, and therapeutic trials in this mouse model suggest postnatal malleability of neurological symptoms. However, 15-30% of individuals with KS1 carry missense variants. To investigate whether missense variants lead to similar phenotypic presentation in mice, we used CRISPR-Cas9 to introduce the KS1 patient variant R5179H, corresponding to R5230H in mice, into C57BL/6NTac animals. Computational and in vitro testing suggested that the R5230H variant does not impair protein stability or enzyme function of KMT2D. Despite a distinct mechanistic basis, our new mouse model (Kmt2d+/R5230H) recapitulated most phenotypes of our prior loss-of-function model, including growth deficiency, craniofacial anomalies and IgA deficiency, but not altered neurological function. Kmt2d+/R5230H mice showed perinatal lethality and a high frequency of unilateral kidney agenesis, a novel phenotype in KS1 mouse models. Kmt2d+/R5230H mice provide a unique opportunity to understand the impact of missense variants on KMT2D function and uncover developmental and perinatal abnormalities in KS1.
Related
- KDM6A Haploinsufficiency Is Insufficient to Disrupt Cochlear Structure and Auditory Function in Mouse Models of Kabuki Syndrome Type 2
- Kabuki Syndrome: Epigenetic Mechanisms, DNA Methylation Signatures, and Diagnostic Advances
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- A mouse model of a rare ASD-implicated patient-derived SCN2A variant
BibTeX
@article{halldorsdottir2026patientderived,
title = {{A patient-derived missense mouse model of Kabuki syndrome 1}},
author = {Sara Tholl Halldorsdottir and Meghna Vinod and Hilmar Orn Gunnlaugsson and Ellen Dagmar Bjornsdottir and Romain Maurice Jacques Lasseur and Teresa Luperchio and Jill A. Fahrner and Agnes Ulfig and Hans Tomas Bjornsson},
journal = {Disease Models \& Mechanisms},
year = {2026},
month = oct,
doi = {10.1242/dmm.052775},
url = {https://doi.org/10.1242/dmm.052775},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A patient-derived missense mouse model of Kabuki syndrome 1
AU - Sara Tholl Halldorsdottir
AU - Meghna Vinod
AU - Hilmar Orn Gunnlaugsson
AU - Ellen Dagmar Bjornsdottir
AU - Romain Maurice Jacques Lasseur
AU - Teresa Luperchio
AU - Jill A. Fahrner
AU - Agnes Ulfig
AU - Hans Tomas Bjornsson
PY - 2026
DA - 2026/10/14
JO - Disease Models & Mechanisms
DO - 10.1242/dmm.052775
UR - https://doi.org/10.1242/dmm.052775
AB - Kabuki syndrome type 1 (KS1) is a rare cause of intellectual disability resulting from heterozygous pathogenic variants in the gene encoding the histone methyltransferase KMT2D. A previously established loss-of-function mouse model of KS1 exhibits key phenotypic features, and therapeutic trials in this mouse model suggest postnatal malleability of neurological symptoms. However, 15-30% of individuals with KS1 carry missense variants. To investigate whether missense variants lead to similar phenotypic presentation in mice, we used CRISPR-Cas9 to introduce the KS1 patient variant R5179H, corresponding to R5230H in mice, into C57BL/6NTac animals. Computational and in vitro testing suggested that the R5230H variant does not impair protein stability or enzyme function of KMT2D. Despite a distinct mechanistic basis, our new mouse model (Kmt2d+/R5230H) recapitulated most phenotypes of our prior loss-of-function model, including growth deficiency, craniofacial anomalies and IgA deficiency, but not altered neurological function. Kmt2d+/R5230H mice showed perinatal lethality and a high frequency of unilateral kidney agenesis, a novel phenotype in KS1 mouse models. Kmt2d+/R5230H mice provide a unique opportunity to understand the impact of missense variants on KMT2D function and uncover developmental and perinatal abnormalities in KS1.
SN - 1754-8403
SN - 1754-8411
ER -