Selected Grantee Publications
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- 12 results found
- Neurological
- CRISPR
- Spectrometry
De Novo and Inherited Variants in DDX39B Cause a Novel Neurodevelopmental Syndrome
Booth et al., Brain. 2025.
https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf035/8004980?login=true
DDX39B is a core component of the TRanscription-EXport (TREX) super protein complex. Recent studies have highlighted the important role of TREX subunits in neurodevelopmental disorders. Researchers describe a cohort of six individuals (male and female) from five families with disease-causing de novo missense variants or inherited splice-altering variants in DDX39B. Three individuals in the cohort are affected by mild to severe developmental delay, hypotonia, history of epilepsy or seizure, short stature, skeletal abnormalities, variable dysmorphic features, and microcephaly. Using a combination of patient genomic and transcriptomic data, in silico modeling, in vitro assays, and in vivo Drosophila and zebrafish models, this study implicates disruption of DDX39B in a novel neurodevelopmental disorder called TREX-complex-related neurodevelopmental syndrome. Supported by ORIP (U54OD030165).
Dysregulation of mTOR Signalling Is a Converging Mechanism in Lissencephaly
Zhang et al., Nature. 2025.
https://pubmed.ncbi.nlm.nih.gov/39743596
Lissencephaly (smooth brain) is a rare genetic condition, with such symptoms as epilepsy and intellectual disability and a median life expectancy of 10 years. This study reveals that reduced activity of the mTOR pathway may be a common cause of lissencephaly. Researchers used laboratory-grown brain models (organoids) and sequencing and spectrometry techniques to identify decreased mTOR activation in two types of lissencephaly disorders: p53-induced death domain protein 1 and Miller–Dieker lissencephaly syndrome. Pharmacological activation of mTOR signaling with a brain-selective mTORC1 activator molecule, NV-5138, prevented and reversed the morphological and functional defects in organoids. These findings suggest that mTOR dysregulation contributes to the development of lissencephaly spectrum disorders and highlight a potential druggable pathway for therapy. Supported by ORIP (S10OD018034, S10OD019967, S10OD030363), NCATS, NHGRI, NICHD, NIDA, NIGMS, NIMH, and NINDS.
Peripherally Mediated Opioid Combination Therapy in Mouse and Pig
Peterson et al., The Journal of Pain. 2025.
https://pubmed.ncbi.nlm.nih.gov/39542192
This study evaluates novel opioid combinations for pain relief with reduced side effects. Researchers investigated loperamide (a μ-opioid agonist) with either oxymorphindole or N‑benzyl-oxymorphindole—both δ-opioid receptor partial agonists—in mice (male and female) and pigs (male). These combinations produced synergistic analgesia across species without causing adverse effects or respiratory depression. The therapies significantly reduced hypersensitivity in post-injury models, outperforming morphine alone. These findings suggest that peripherally acting opioid combinations can offer effective, safer alternatives for pain management, potentially lowering opioid misuse and side effects. This approach could improve clinical strategies for treating chronic and acute pain with limited central opioid exposure. Supported by ORIP (T32OD010993), NHLBI, and NIDA.
Plural Molecular and Cellular Mechanisms of Pore Domain KCNQ2 Encephalopathy
Abreo et al., eLife. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11703504
This study investigates the cellular and molecular mechanisms underlying KCNQ2 encephalopathy, a severe type of early-onset epilepsy caused by mutations in the KCNQ2 gene. Researchers describe a case study of a child with a specific KCNQ2 gene mutation, G256W, and found that it disrupts normal brain activity, leading to seizures and developmental impairments. Male and female Kcnq2G256W/+ mice have reduced KCNQ2 protein levels, epilepsy, brain hyperactivity, and premature deaths. As seen in the patient study, ezogabine treatment rescued seizures in mice, suggesting a potential treatment avenue. These findings provide important insights into KCNQ2-related epilepsy and highlight possible therapeutic strategies. Supported by ORIP (U54OD020351, S10OD026804, U54OD030187), NCI, NHLBI, NICHD, NIGMS, NIMH, and NINDS.
Impaired Axon Initial Segment Structure and Function in a Model of ARHGEF9 Developmental and Epileptic Encephalopathy
Wang et al., PNAS. 2024.
https://www.pnas.org/doi/10.1073/pnas.2400709121
Researchers developed a mouse model carrying the G55A missense variant identified in ARHGEF9 patients with severe epilepsy and neurodevelopmental phenotypes. Using male Arhgef9G55A mice, this study examined behavioral, molecular, and electrophysiological phenotypes in the Arhgef9G55A model of developmental and epileptic encephalopathies (DEE). Researchers found that the G55A variant causes disruption of inhibitory postsynaptic organization and axon initial segment (AIS) architecture, leading to impairment of both synaptic transmission and action potential generation. The effects of Arhgef9G55A on neuronal function affect both intrinsic and synaptic excitability and preferentially impair AIS. These findings indicate a novel pathological mechanism of DEE and represent a unique example of a neuropathological condition converging from AIS dysfunctions. Supported by ORIP (U54OD020351, U54OD030187, U54OD020351, S10OD026974) and NINDS.
Impaired Skeletal Development by Disruption of Presenilin-1 in Pigs and Generation of Novel Pig Models for Alzheimer's Disease
Uh et al., Journal of Alzheimer's Disease. 2024.
https://pubmed.ncbi.nlm.nih.gov/39177593/
This study explored the effects of presenilin 1 (PSEN1) disruption on vertebral malformations in male and female PSEN1 mutant pigs. Researchers observed significant skeletal impairments and early deaths in pigs with a PSEN1 null mutation, mirroring phenotypes seen in mouse models of Alzheimer’s disease (AD). This porcine model provides valuable insights into pathological hallmarks of PSEN1 mutations in AD, offering a robust platform of therapeutic exploration. The findings establish pigs as an essential translational model for AD, enabling advanced studies on pathophysiology and treatment development for human skeletal and neurological conditions. Supported by ORIP (U42OD011140), NHLBI, NIA, NIAID.
The Role of ATP Citrate Lyase in Myelin Formation and Maintenance
Schneider et al., Glia. 2024.
https://pubmed.ncbi.nlm.nih.gov/39318247/
Myelin formation by Schwann cells is critical for peripheral nervous system development and long-term neuronal function. The study examined how acetyl coenzyme A (acetyl-CoA), essential for lipid synthesis in myelin, is derived, with a focus on mitochondrial ATP citrate lysate (ACLY). By using both sexes in a Schwann cell–specific ACLY knockout mouse model, the authors reported that ACLY plays a role in acetyl-CoA supply for myelin maintenance but not myelin formation. ACLY is necessary for sustaining myelin gene expression and preventing nerve injury pathways. This work highlights a unique dependency on mitochondrial acetyl-CoA for Schwann cell integrity, providing insights into lipid metabolism in neuronal repair. Supported by ORIP (T35OD011078), NICHD, and NINDS.
Commentary: The International Mouse Phenotyping Consortium: High-Throughput In Vivo Functional Annotation of the Mammalian Genome
Lloyd, Mammalian Genome. 2024.
https://pubmed.ncbi.nlm.nih.gov/39254744
The International Mouse Phenotyping Consortium (IMPC), a collectively governed consortium of 21 academic research institutions across 15 countries on 5 continents, represents a groundbreaking approach in genetics and biomedical research. Its goal is to create a comprehensive catalog of mammalian gene function that is freely available and equally accessible to the global research community. So far, the IMPC has uncovered the function of thousands of genes about which little was previously known. By 2027, when the current round of funding expires, the IMPC will have produced and phenotyped nearly 12,000 knockout mouse lines representing approximately 60% of the human orthologous genome in mice. This new knowledge has produced numerous insights about the role of genes in health and disease, including informing the genetic basis of rare diseases and positing gene product influences on common diseases. However, as IMPC nears the end of the current funding cycle, its path forward remains unclear. Supported by ORIP (UM1OD023221).
The Mutant Mouse Resource and Research Center (MMRRC) Consortium: The U.S.-Based Public Mouse Repository System
Agca et al., Mammalian Genome. 2024.
https://link.springer.com/article/10.1007/s00335-024-10070-3
The MMRRC has been the nation’s preeminent public repository and distribution archive of mutant mouse models for 25 years. The Consortium, with support from NIH, facilitates biomedical research by identifying, acquiring, evaluating, characterizing, preserving, and distributing a variety of mutant mouse strains to investigators around the world. Since its inception, the MMRRC has fulfilled more than 20,000 orders from 13,651 scientists at 8,441 institutions worldwide. Today, the MMRRC maintains an archive of mice, cryopreserved embryos and sperm, embryonic stem-cell lines, and murine monoclonal antibodies for nearly 65,000 alleles. The Consortium also provides scientific consultation, technical assistance, genetic assays, microbiome analysis, analytical phenotyping, pathology, husbandry, breeding and colony management, and more. Supported by ORIP (U42OD010918, U42OD010924, U42OD010983).
Intrinsic Link Between PGRN and GBA1 D409V Mutation Dosage in Potentiating Gaucher Disease
Lin et al., Human Molecular Genetics. 2024.
https://doi.org/10.1093/hmg/ddae113
Gaucher disease (GD) is an autosomal recessive disorder and one of the most common lysosomal storage diseases. GD is caused by mutations in the GBA1 gene that encodes glucocerebrosidase (GCase), a lysosomal protein involved in glyocolipid metabolism. Progranulin (PGRN, encoded by GRN) is a modifier of GCase, and GRN mutant mice exhibit a GD-like phenotype. The researchers in this study aimed to understand the relationship between GCase and PGRN. They generated a panel of mice with various doses of the GBA1 D409V mutation in the GRN-/- background and characterized the animals’ disease progression using biochemical, pathological, transcriptomic, and neurobehavioral analyses. Homozygous (GRN-/-, GBA1 D409V/D409V) and hemizygous (GRN-/-, GBA1 D409V/null) animals exhibited profound inflammation and neurodegeneration compared to PG96 wild-type mice. Compared to homozygous mice, hemizygous mice showed more profound phenotypes (e.g., earlier onset, increased tissue fibrosis, shorter life span). These findings offer insights into GD pathogenesis and indicate that GD severity is affected by GBA1 D409V dosage and the presence of PGRN. Supported by ORIP (R21OD033660) and NINDS.