ArticleAmerican journal of human genetics2020
Bi-allelic LoF NRROS Variants Impairing Active TGF-β1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification.
Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 31 citations in OpenAlex.
- Differences in mRNA expression of neuroinflammation-related genes in the temporal lobe of patients with drug-resistant focal epilepsy.Epileptic disorders : international epilepsy journal with videotape · 2026Article
- Driver or passenger? A new assessment of genes in the schizophrenia-associated 3q29 deletion locus for contribution to neurodevelopmental disorders.Journal of neurodevelopmental disorders · 2026Review
- De novo pathogenic CSF1R variant implicates microglial dysfunction in pathogenesis of febrile infection-related epilepsy syndrome.Epilepsia · 2025Article
- Drivers and shapers of macrophages specification in the developing brain.Current opinion in immunology · 2025Review
- Neurodegeneration, Intracranial Calcifications, Microcephaly and Drug-Resistant Epilepsy Caused by a Novel Homozygous Missense Variant in theInternational medical case reports journal · 2025Article
- Human ITGAV variants are associated with immune dysregulation, brain abnormalities, and colitis.The Journal of experimental medicine · 2024Article
- Vitamin D Supplementation: Effect on Cytokine Profile in Multiple Sclerosis.Journal of clinical medicine · 2024Review
- Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- Microglia and Brain Disorders: The Role of Vitamin D and Its Receptor.International journal of molecular sciences · 2023Review
- Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice.Developmental medicine and child neurology · 2023Article
- Mitochondrial Dysfunction and Oxidative Stress in Hereditary Ectopic Calcification Diseases.International journal of molecular sciences · 2022Review
- Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration.Neurogenetics · 2022Article
- Loss of LRRC33-Dependent TGFβ1 Activation Enhances Antitumor Immunity and Checkpoint Blockade Therapy.Cancer immunology research · 2022Article
- The Interplay Between Brain Vascular Calcification and Microglia.Frontiers in aging neuroscience · 2022Review
- Characterizing the Genetic Architecture of Parkinson's Disease in Latinos.Annals of neurology · 2021Article
- The multicellular interplay of microglia in health and disease: lessons from leukodystrophy.Disease models & mechanisms · 2021Review
- Review
- The Immune System's Role in the Consequences of Mild Traumatic Brain Injury (Concussion).Frontiers in immunology · 2021Review
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Authors and funding
17 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat-containing protein that uniquely associates with latent transforming growth factor beta-1 (TGF- β1) and anchors it on the cell surface; this anchoring is required for activation of TGF-β1 in macrophages and microglia. We report six individuals from four families with bi-allelic variants in NRROS. All affected individuals had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination. The clinical course in affected individuals began with normal development or mild developmental delay, and the onset of seizures occurred within the first year of life, followed by developmental regression. Intracranial calcification was detected in three individuals. The phenotypic features in affected individuals are consistent with those observed in the Nrros knockout mouse, and they overlap with those seen in the human condition associated with TGF-β1 deficiency. The disease-causing NRROS variants involve two significant functional NRROS domains. These variants result in aberrant NRROS proteins with impaired ability to anchor latent TGF-β1 on the cell surface. Using confocal microscopy in HEK293T cells, we demonstrate that wild-type and mutant NRROS proteins co-localize with latent TGF-β1 intracellularly. However, using flow cytometry, we show that our mutant NRROS proteins fail to anchor latent TGF-β1 at the cell surface in comparison to wild-type NRROS. Moreover, wild-type NRROS rescues the defect of our disease-associated mutants in presenting latent TGF-β1 to the cell surface. Taken together, our findings suggest that loss of NRROS function causes a severe childhood-onset neurodegenerative condition with features suggestive of a disordered response to inflammation.
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