Biology subjects

Durham, E.

Publications and source records attributed to Durham, E..

3 recordsLinked to original sources

bioRxiv2026

A novel preclinical mouse model recapitulates progressive phenotypes of Bryant-Li-Bhoj Syndrome

Bryant-Li-Bhoj Syndrome (BLBS; OMIM: 619720, 619721) is a Mendelian neurogenetic condition, first described in 2020, with a mixed neurodevelopmental/neurodegenerative phenotype and variable systemic features. To date, 100 affected individuals with 74 unique causative variants have been published. Clinical data and prior functional work in multiple model systems have emphasized the utility of interrogating the pathogenesis of multiple causal variants to identify a convergent, therapeutically targetable mechanism. Additionally, the ability to evaluate the efficacy of future therapeutics relies on the availability of a robustly validated preclinical model. Here, we characterize the developmental and neurobehavioral phenotypes of a novel BLBS mouse model harboring one of the most recurrent causative variants (h3-3a p.T45I). H3.3T45I mice recapitulate the BLBS natural history: perinatal growth restriction, delayed developmental milestones, and progressive motor and gait impairments. Adult mice additionally display craniofacial differences, impaired nest building, hyperactivity in a social context, and male-specific elevated aggression. The non-invasive, clinically translatable endpoints established here provide a validated preclinical platform for evaluating therapeutics for a community whose current standard of care is symptom management. Summary StatementA new mouse model mirrors the developmental delays, motor decline, and behavioral changes seen in individuals with this rare, progressive genetic brain disorder, providing a foundation for testing future therapies.

genetics↗

bioRxiv2025

TBCK Deficiency Alters Ribosomal Function, RNA Splicing, and miRNA Networks: Insights from Multi-Omics Analyses

TBC1 domain-containing kinase (TBCK) is an important protein with implications in brain development. Biallelic variants in the TBCK gene are known to cause TBCK-related neurodevelopmental disorder (OMIM #616900) [1], a rare genetic multisystemic disease characterized by developmental delay, variable developmental regression, seizures, and premature death in late childhood for which no cure is currently available. Though previous work has provided a better understanding of the proteins role, the mechanism for how TBCK variants affect gene expression and protein regulation has remained understudied. To better understand the impact of these alterations, and using an unbiased approach, we employed the power of multi-omics to define the cellular consequences at the transcript and protein level. Our comprehensive analysis uncovered significant disruptions in ribosomal and translation-related pathways with widespread alternative splicing defects, and key miRNA changes that validate previously reported molecular findings. This work provides a clearer molecular framework for TBCK dysfunction in TBCK-/- cells and offers a valuable foundation to identify potential therapeutic targets.

genetics↗

bioRxiv2023

Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency

Branched chain ketoacid dehydrogenase kinase (BCKDK) deficiency is a recently described inherited neurometabolic disorder of branched chain amino acid (BCAA) metabolism implying increased BCAA catabolism. It has been hypothesized that a severe reduction in systemic BCAA levels underlies the disease pathophysiology, and that BCAA supplementation may ameliorate disease phenotypes. To test this hypothesis, we characterized a recent mouse model of BCKDK deficiency and evaluated the efficacy of enteral BCAA supplementation in this model. Surprisingly, BCAA supplementation exacerbated neurodevelopmental deficits and did not correct biochemical abnormalities despite increasing systemic BCAA levels. These data suggest that aberrant flux through the BCAA catabolic pathway, not just BCAA insufficiency, may contribute to disease pathology. In support of this conclusion, genetic re-regulation of BCAA catabolism, through Dbt haploinsufficiency, partially rescued biochemical and behavioral phenotypes in BCKDK deficient mice. Collectively, these data raise into question assumptions widely made about the pathophysiology of BCKDK insufficiency and suggest a novel approach to develop potential therapies for this disease.

molecular biology↗