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Structures of Respiratory Syncytial Virus G Bound to Broadly Reactive Antibodies Provide Insights into Vaccine Design
Juarez et al., Scientific Reports. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11906780
Respiratory syncytial virus (RSV) is one of the leading causes of severe lower respiratory infection in both infants and older adults. RSV viral entry and modulation of the host immunity is mediated by attachment glycoprotein RSV G binding to the chemokine receptor CX3CR1. Antibodies isolated from RSV-exposed individuals have shown great promise in host protection. Researchers using an ORIP-funded electron microscope, in conjunction with X-ray crystallography, have solved the structure of these antibodies bound to the RSV G protein and identified a novel dual antibody binding region. The presence of dual antibody binding sites indicates the potential to elicit antibody responses that resist virus escape. These findings will help develop next-generation RSV prophylactics and provide insight for new concepts in vaccine design. Supported by ORIP (S10OD027012, S10OD025097), NIAID, NHGRI, and NIGMS.
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.
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.
Identifying Potential Dietary Treatments for Inherited Metabolic Disorders Using Drosophila Nutrigenomics
Martelli et al., Cell Reports. 2024.
https://www.sciencedirect.com/science/article/pii/S221112472400189X?via%3Dihub=
Inherited metabolic disorders are known to cause severe neurological impairment and child mortality and can sometimes respond to dietary treatment; however, a suitable paradigm for testing diets is lacking for developing effective dietary treatment. In this study, researchers found that 26 of 35 Drosophila amino acid disorder models screened for disease–diet interactions displayed diet-altered development and/or survival. Among these models, researchers showed that dietary cysteine depletion normalizes metabolic profile and rescues development, neurophysiology, behavior, and life span in a model for isolated sulfite oxidase deficiency. These findings demonstrate the value of using Drosophila in studying diet-sensitive metabolic disorders and developing potential dietary therapies. Supported by ORIP (R24OD031447) and NHGRI.
A Defect in Mitochondrial Fatty Acid Synthesis Impairs Iron Metabolism and Causes Elevated Ceramide Levels
Dutta et al., Nature Metabolism. 2023.
https://pubmed.ncbi.nlm.nih.gov/37653044/
Human mitochondrial enoyl coenzyme A reductase (Mecr), required for the last step of mitochondrial fatty acid synthesis (mtFAS), is linked to pediatric-onset neurodegeneration, but with unknown mechanisms. Researchers investigated phenotypes of mecr mutants in Drosophila and human-derived fibroblasts. They found that loss of function of Mecr in the whole body resulted in a defect in Fe-S cluster biogenesis and increased iron levels, leading to elevated ceramide levels and lethality in flies. Similar elevated ceramide levels and impaired iron homeostasis were observed human-derived fibroblasts with Mecr deficiency. Neuronal loss of Mecr led to progressive neurodegeneration in flies. This study pointed out a mechanistic link between mtFAS and neurodegeneration through Mecr. Supported by ORIP (R24OD022005, R24OD031447), NICHD, and NINDS.
De Novo Variants in EMC1 Lead to Neurodevelopmental Delay and Cerebellar Degeneration and Affect Glial Function in Drosophila
Chung et al., Human Molecular Genetics. 2022.
https://www.doi.org/10.1093/hmg/ddac053
Variants in EMC1, which encodes a subunit of the endoplasmic reticulum (ER)–membrane protein complex (EMC), are associated with developmental delay in children. Functional consequences of these variants are poorly understood. The investigators identified de novo variants in EMC1 in three children affected by global developmental delay, hypotonia, seizures, visual impairment, and cerebellar atrophy. They demonstrated in Drosophila that these variants are loss-of-function alleles and lead to lethality when expressed in glia but not in neurons. This work suggests the causality of EMC variants in disease. Supported by ORIP (R24OD022005, R24OD031447), NINDS, and NICHD.
A Novel DPH5-Related Diphthamide-Deficiency Syndrome Causing Embryonic Lethality or Profound Neurodevelopmental Disorder
Shankar et al., Genetics in Medicine. 2022.
https://www.doi.org/10.1016/j.gim.2022.03.014
Neurodevelopmental disorders (NDDs) affect more than 3% of the pediatric population and often have associated neurologic or multisystem involvement. The underlying genetic etiology of NDDs remains unknown in many individuals. Investigators characterized the molecular basis of NDDs in children of both sexes with nonverbal NDDs from three unrelated families with distinct overlapping craniofacial features. The investigators also used a mouse model of both sexes to determine the pathogenicity of variants of uncertain significance, as well as genes of uncertain significance, to advance translational genomics and provide precision health care. They identified several variants in DPH5 as a potential cause of profound NDD. Their findings provide strong clinical, biochemical, and functional evidence for DPH5 variants as a novel cause of embryonic lethality or profound NDD with multisystem involvement. Based on these findings, the authors propose that “DPH5-related diphthamide deficiency syndrome” is a novel autosomal-recessive Mendelian disorder. Supported by ORIP (K01OD026608, U42OD012210) and NHGRI.
Heritability of Social Behavioral Phenotypes and Preliminary Associations with Autism Spectrum Disorder Risk Genes in Rhesus Macaques: A Whole Exome Sequencing Study
Gunter et al., Autism Research. 2022.
https://onlinelibrary.wiley.com/doi/full/10.1002/aur.2675
Investigators quantified individual variation in social interactions among juvenile rhesus macaques of both sexes using both a standard macaque ethogram (a catalogue of animal behavior over time) and a macaque-relevant modification of the human Social Responsiveness Scale to study genetic influences on key aspects of social behavior and interactions. The analyses demonstrate that various aspects of juvenile social behavior exhibit significant genetic heritability, with quantitative genetic effects similar to autism spectrum disorder (ASD) in human children. The significant genetic and sequencing data may be used to examine potential genetic associations with human ASD. Supported by ORIP (P51OD011132), NHGRI and NIMH.
A Novel Non-Human Primate Model of Pelizaeus-Merzbacher Disease
Sherman et al., Neurobiology of Disease. 2021.
https://www.sciencedirect.com/science/article/pii/S096999612100214X
Pelizaeus-Merzbacher disease (PMD) in humans is a severe hypomyelinating disorder of the central nervous system (CNS) linked to mutations in the proteolipid protein-1 (PLP1) gene. Investigators report on three spontaneous cases of male neonatal rhesus macaques (RMs) with clinical symptoms of hypomyelinating disease. Genetic analysis revealed that the parents of these related RMs carried a rare, hemizygous missense variant in exon 5 of the PLP1 gene. These RMs represent the first reported NHP model of PMD, providing an opportunity for studies to promote myelination in pediatric hypomyelinating diseases, as other animal models for PMD do not fully mimic the human disorder. Supported by ORIP (R24OD021324, P51OD011092, and S10OD025002) and NINDS.
Loss of Gap Junction Delta-2 (GJD2) Gene Orthologs Leads to Refractive Error in Zebrafish
Quint et al., Communications Biology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34083742/
Myopia is the most common developmental disorder of juvenile eyes. Although little is known about the functional role of GJD2 in refractive error development, the authors find that depletion of gjd2a (Cx35.5) or gjd2b (Cx35.1) orthologs in zebrafish cause changes in eye biometry and refractive status. Their immunohistological and scRNA sequencing studies show that Cx35.5 (gjd2a) is a retinal connexin; its depletion leads to hyperopia and electrophysiological retina changes. They found a lenticular role; lack of Cx35.1 (gjd2b) led to a nuclear cataract that triggered axial elongation. The results provide functional evidence of a link between gjd2 and refractive error. Supported by ORIP (R24OD026591), NIGMS, and NINDS.