{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:49:49Z","timestamp":1791978589816,"version":"4.4.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"24","license":[{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The high-affinity copper transporter CTR1 is encoded by CTR1 (SLC31A1), a gene locus for which no detailed genotype\u2013phenotype correlations have previously been reported. We describe identical twin male infants homozygous for a novel missense variant NM_001859.4:c.284\u00a0G\u2009&amp;gt;\u2009A (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\u2019 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\u2019 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.<\/jats:p>","DOI":"10.1093\/hmg\/ddac156","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T15:34:29Z","timestamp":1659368069000},"page":"4121-4130","source":"Crossref","is-referenced-by-count":48,"title":["Newly identified disorder of copper metabolism caused by variants in <i>CTR1<\/i>, a high-affinity copper transporter"],"prefix":"10.1093","volume":"31","author":[{"given":"Spyros","family":"Batzios","sequence":"first","affiliation":[{"name":"Department of Paediatric Metabolic Medicine , Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galit","family":"Tal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics B , Metabolic Clinic, Ruth Rappaport Children's Hospital, Rambam Health Care Campus and The Ruth and Bruce Rappaport Faculty of Medicine, 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Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Mandel","sequence":"additional","affiliation":[{"name":"Department of Genetics , Western Galilee Medical Center, Nahariya 2210001 , Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J","family":"Steinbach","sequence":"additional","affiliation":[{"name":"Bioinformatics and Computational Biosciences Branch , Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Yi","sequence":"additional","affiliation":[{"name":"Section on Translational Neuroscience , Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Summer R","family":"Fair","sequence":"additional","affiliation":[{"name":"Steve and Cindy Rasmussen Institute for Genomic Medicine , Nationwide Children\u2019s Hospital, Columbus, OH 43205 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark E","family":"Hester","sequence":"additional","affiliation":[{"name":"Steve and Cindy Rasmussen Institute for Genomic Medicine , Nationwide Children\u2019s Hospital, Columbus, OH 43205 , USA"},{"name":"Department of Pediatrics , The Ohio State University College of Medicine, Columbus, OH 43210 , USA"},{"name":"Department of Neuroscience , The Ohio State University Wexner Medical Center, Columbus, OH 43210 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthi","family":"Drousiotou","sequence":"additional","affiliation":[{"name":"Department of Biochemical Genetics , Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular 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