Biology subjects

Halldorsdottir, S. T.

Publications and source records attributed to Halldorsdottir, S. T..

3 recordsLinked to original sources

bioRxiv2026

Loss of KMT2D accelerates hypertrophic chondrocyte differentiation and senescence by increasing mitochondrial ROS production

Longitudinal bone growth occurs through endochondral ossification, which is accompanied by the differentiation of chondrocytes in the growth plate. Disruption in chondrocyte maturation can lead to skeletal growth abnormalities, such as those observed in Kabuki syndrome type 1 (KS1), a genetic disorder caused by heterozygous pathogenic variants in the KMT2D gene. KS1 patients exhibit postnatal growth deficiency, craniofacial hypoplasia, and skeletal deformities, yet the mechanisms underlying these phenotypic manifestations remain poorly understood. Our study investigated the effects of KMT2D deficiency on chondrocyte maturation and identified premature chondrocyte hypertrophy as a key driver of skeletal abnormalities in KS1. We previously observed reduced femur and tibia length in a KS1 mouse model, along with altered growth plate architecture, particularly affecting the heights of the proliferative and hypertrophic zones. Here, we show that KMT2D-deficient chondrocytes exhibit accelerated differentiation and early senescence upon exposure to supraphysiological oxygen levels (20% O2). These pathological changes were linked to increased mitochondrial reactive oxygen species (ROS) production likely caused by deficiencies in electron transport chain function, leading to oxidative stress and premature hypertrophy. Pharmacological ROS neutralization or hypoxic conditions mitigated these effects, restoring normal chondrocyte differentiation and preventing premature ossification. These findings demonstrate that KMT2D loss induces oxidative stress-driven chondrocyte hypertrophy, disrupting the balance of cartilage growth and ossification. Our study provides crucial mechanistic insights into KS1-associated skeletal abnormalities and suggests mitochondrial ROS regulation as a potential therapeutic avenue.

molecular biology↗

bioRxiv2025

A patient derived missense mouse model of Kabuki syndrome 1

Kabuki syndrome (KS) 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 KS exhibits key phenotypic features, and therapeutic trials in this mouse model suggest postnatal malleability of neurological symptoms. However, 15-30% of individuals with KS, carry missense variants. To investigate whether missense variants lead to similar phenotypic presentation in mice, we used CRISPR-Cas9 to introduce the KS patient variant R5230H into C57BL/6NTac. Computational and in vitro testing suggests that the R5230H variant does not impair protein stability or loss of enzyme function of KMT2D. Despite a distinct mechanistic basis, our new mouse model (Kmt2d+/R5230H) recapitulates most phenotypes of our prior loss-of-function model, including growth deficiency, craniofacial anomalies, and IgA deficiency but not altered neurological function. Kmt2d+/R5230Hmice show perinatal lethality and a high frequency of unilateral kidney agenesis, a novel phenotype in KS 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 KS. Summary statementA novel Kabuki syndrome missense mouse model with intact KMT2D enzymatic function shares most features with prior KS models, except disruption of adult neurogenesis, and exhibits novel unilateral kidney loss.

genetics↗

bioRxiv2023

SMYD5 is a novel epigenetic gatekeeper of the mild hypothermia response

The mild hypothermia response (MHR) maintains organismal homeostasis during cold exposure and is thought to be critical for the neuroprotection documented with therapeutic hypothermia. To date, little is known about the transcriptional regulation of the MHR. We utilize a forward CRISPR-Cas9 mutagenesis screen to identify the histone lysine methyltransferase SMYD5 as a regulator of the MHR. SMYD5 represses the key MHR gene SP1 at euthermia. This repression correlates with temperature-dependent levels of H3K36me3 at the SP1-locus and globally, indicating that the mammalian MHR is regulated at the level of histone modifications. We have identified 37 additional SMYD5 regulated temperature-dependent genes, suggesting a broader MHR-related role for SMYD5. Our study provides an example of how histone modifications integrate environmental cues into the genetic circuitry of mammalian cells and provides insights that may yield therapeutic avenues for neuroprotection after catastrophic events.

genetics↗