ArticleHuman molecular genetics2022
Newly identified disorder of copper metabolism caused by variants in CTR1, a high-affinity copper transporter.
Article in Human molecular genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 40 citations in OpenAlex.
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- Cu(I) and Cu(II) binding by hyperactive variants of the human CTR1 N-terminus: Insights from cellular and model peptide studies.Journal of inorganic biochemistry · 2026Article
- Cellular and subcellular localization of the copper transporter CTR1 in human postmortem hippocampus and striatum.Scientific reports · 2026Article
- Copper in Human Health and Disease: Insights from Inherited Disorders.Physiology (Bethesda, Md.) · 2026Review
- Distinct signaling mechanisms and proteome phenotypes are elicited by compartment-specific genetic defects of copper homeostasis.bioRxiv : the preprint server for biology · 2026Article
- A C. elegans model of copper deficiency: Dietary interventions rescue CTR1/CHCA-1 copper transporter mutant phenotype.PLoS genetics · 2026Article
- Harnessing copper: Innovative approaches to combat neurodegenerative diseases and cancer (Review).International journal of molecular medicine · 2026Review
- Human CTR1 Through the Ages: Milestones and Emerging Roles in Disease and Therapy.Biomolecules · 2025Review
- Role and mechanisms of cuproptosis in the pathogenesis of Wilson's disease (Review).International journal of molecular medicine · 2025Review
- A primer on copper biology in the brain.Neurobiology of disease · 2025Review
- Adaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration.Molecular biology of the cell · 2025Article
- Prion protein promotes copper toxicity in Wilson disease.Nature communications · 2025Article
- Elesclomol rescues mitochondrial copper deficiency in disease models without triggering cuproptosis.The Journal of pharmacology and experimental therapeutics · 2025Article
- Cuproptosis-related genes and agents: implications in tumor drug resistance and future perspectives.Frontiers in pharmacology · 2025Review
- Clinical and molecular characterization of SLC31A1-related developmental and epileptic encephalopathy: insights from 13 new cases.Brain communications · 2025Article
- Mammalian copper homeostasis: physiological roles and molecular mechanisms.Physiological reviews · 2025Review
- Copper supplementation alleviates hypoxia‑induced ferroptosis and oxidative stress in neuronal cells.International journal of molecular medicine · 2024Article
- Adaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration.bioRxiv : the preprint server for biology · 2024Article
- Decreased spinal cord motor neuron numbers in mice depleted of central nervous system copper.Metallomics : integrated biometal science · 2024Article
- The physiological and pathophysiological roles of copper in the nervous system.The European journal of neuroscience · 2024Review
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Authors and funding
15 authors at 10 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The high-affinity copper transporter CTR1 is encoded by CTR1 (SLC31A1), a gene locus for which no detailed genotype-phenotype correlations have previously been reported. We describe identical twin male infants homozygous for a novel missense variant NM_001859.4:c.284 G > A (p.Arg95His) in CTR1 with a distinctive autosomal recessive syndrome of infantile seizures and neurodegeneration, consistent with profound central nervous system copper deficiency. We used clinical, biochemical and molecular methods to delineate the first recognized examples of human CTR1 deficiency. These included clinical phenotyping, brain imaging, assays for copper, cytochrome c oxidase (CCO), and mitochondrial respiration, western blotting, cell transfection experiments, confocal and electron microscopy, protein structure modeling and fetal brain and cerebral organoid CTR1 transcriptome analyses. Comparison with two other critical mediators of cellular copper homeostasis, ATP7A and ATP7B, genes associated with Menkes disease and Wilson disease, respectively, revealed that expression of CTR1 was highest. Transcriptome analyses identified excitatory neurons and radial glia as brain cell types particularly enriched for copper transporter transcripts. We also assessed the effects of Copper Histidinate in the patients' cultured cells and in the patients, under a formal clinical protocol. Treatment normalized CCO activity and enhanced mitochondrial respiration in vitro, and was associated with modest clinical improvements. In combination with present and prior studies, these infants' clinical, biochemical and molecular phenotypes establish the impact of this novel variant on copper metabolism and cellular homeostasis and illuminate a crucial role for CTR1 in human brain development. CTR1 deficiency represents a newly defined inherited disorder of brain copper metabolism.
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