{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T19:22:25Z","timestamp":1778181745938,"version":"3.51.4"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T00:00:00Z","timestamp":1660262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01HD093570-01A1"],"award-info":[{"award-number":["1R01HD093570-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS095884"],"award-info":[{"award-number":["R01NS095884"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R33NS104384"],"award-info":[{"award-number":["R33NS104384"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R33NS106087"],"award-info":[{"award-number":["R33NS106087"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Reference Network for Rare Neurological Diseases","award":["739510"],"award-info":[{"award-number":["739510"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,19]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hypomyelinating leukodystrophies comprise a subclass of genetic disorders with deficient myelination of the CNS white matter. Here we report four unrelated families with a hypomyelinating leukodystrophy phenotype harbouring variants in TMEM163 (NM_030923.5). The initial clinical presentation resembled Pelizaeus\u2013Merzbacher disease with congenital nystagmus, hypotonia, delayed global development and neuroimaging findings suggestive of significant and diffuse hypomyelination. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant. TMEM163 is highly expressed in the CNS particularly in newly myelinating oligodendrocytes and was recently revealed to function as a zinc efflux transporter. All the variants identified lie in highly conserved residues in the cytoplasmic domain of the protein, and functional in vitro analysis of the mutant protein demonstrated significant impairment in the ability to efflux zinc out of the cell. Expression of the mutant proteins in an oligodendroglial cell line resulted in substantially reduced mRNA expression of key myelin genes, reduced branching and increased cell death. Our findings indicate that variants in TMEM163 cause a hypomyelinating leukodystrophy and uncover a novel role for zinc homeostasis in oligodendrocyte development and myelin formation.<\/jats:p>","DOI":"10.1093\/brain\/awac295","type":"journal-article","created":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T02:17:39Z","timestamp":1660270659000},"page":"4202-4209","source":"Crossref","is-referenced-by-count":20,"title":["Variants in the zinc transporter<i>TMEM163<\/i>cause a hypomyelinating leukodystrophy"],"prefix":"10.1093","volume":"145","author":[{"given":"Michelle C","family":"do Rosario","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education , Manipal , India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guillermo Rodriguez","family":"Bey","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh , Pittsburgh, Pennsylvania , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce","family":"Nmezi","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh , Pittsburgh, Pennsylvania , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh , Pittsburgh, Pennsylvania , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Talia","family":"Oranburg","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh , Pittsburgh, Pennsylvania , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana S A","family":"Cohen","sequence":"additional","affiliation":[{"name":"Genomic Medicine Center, Children\u2019s Mercy , Kansas City, MO 64108 , USA"},{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Mercy , Kansas City, MO 64108 , USA"},{"name":"School of Medicine Serves, University of Missouri-Kansas City School of Medicine , Kansas City, MO 64108 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2474-7857","authenticated-orcid":false,"given":"Keith A","family":"Coffman","sequence":"additional","affiliation":[{"name":"Division of Neurology, Movement Disorders Clinic, Tourette Syndrome Center of Excellence, Children\u2019s Mercy Hospital , Kansas City, Missouri , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maya R","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirill","family":"Kiselyov","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quinten","family":"Waisfisz","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Amsterdam University Medical Centers, VU University Amsterdam, and Amsterdam Neuroscience , Amsterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myrthe T","family":"Flohil","sequence":"additional","affiliation":[{"name":"Department of Neurology, Noordwest ziekenhuisgroep , Wilhelminalaan Alkmaar , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shahyan","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Department of Neuroimaging and Interventional Radiology, STAR Institute of Neurosciences, STAR Hospitals , Hyderabad , India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5664-7987","authenticated-orcid":false,"given":"Jill A","family":"Rosenfeld","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, Texas , USA"},{"name":"Baylor Genetics Laboratories , Houston, Texas , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro","family":"Iglesias","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Columbia University Irving Medical Center , New York, New York , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katta Mohan","family":"Girisha","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education , Manipal , India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1721-0728","authenticated-orcid":false,"given":"Nicole I","family":"Wolf","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma\u2019s Children\u2019s Hospital, and Amsterdam Neuroscience, Cellular & Molecular Mechanisms , Amsterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quasar Saleem","family":"Padiath","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh , Pittsburgh, Pennsylvania , USA"},{"name":"Department of Neurobiology, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2471-4094","authenticated-orcid":false,"given":"Anju","family":"Shukla","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education , Manipal , India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,8,12]]},"reference":[{"key":"2023053018583377000_awac295-B1","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.ymgme.2015.01.006","article-title":"Case definition and classification of leukodystrophies and leukoencephalopathies","volume":"114","author":"Vanderver","year":"2015","journal-title":"Mol Genet Metab"},{"key":"2023053018583377000_awac295-B2","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/S1474-4422(19)30143-7","article-title":"Diagnosis, prognosis, and treatment of leukodystrophies","volume":"18","author":"van der Knaap","year":"2019","journal-title":"Lancet Neurol"},{"key":"2023053018583377000_awac295-B3","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.ymgme.2014.12.434","article-title":"A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies","volume":"114","author":"Parikh","year":"2015","journal-title":"Mol Genet Metab"},{"key":"2023053018583377000_awac295-B4","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s41582-020-00432-1","article-title":"Hypomyelinating leukodystrophies\u2014Unravelling myelin biology","volume":"17","author":"Wolf","year":"2021","journal-title":"Nat Rev Neurol"},{"key":"2023053018583377000_awac295-B5","doi-asserted-by":"crossref","DOI":"10.1016\/j.abb.2019.108166","article-title":"Transmembrane 163 (TMEM163) protein effluxes zinc","volume":"677","author":"Sanchez","year":"2019","journal-title":"Arch Biochem Biophys"},{"key":"2023053018583377000_awac295-B6","first-page":"9.31.1","article-title":"Matchmaker exchange","volume":"95","author":"Sobreira","year":"2017","journal-title":"Curr Protoc Hum Genet"},{"key":"2023053018583377000_awac295-B7","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1111\/jnc.13886","article-title":"The synaptic vesicle protein SV31 assembles into a dimer and transports Zn(2)","volume":"140","author":"Waberer","year":"2017","journal-title":"J Neurochem"},{"key":"2023053018583377000_awac295-B8","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1021\/ja011774y","article-title":"Detection and imaging of zinc secretion from pancreatic beta-cells using a new fluorescent zinc indicator","volume":"124","author":"Gee","year":"2002","journal-title":"J Am Chem Soc"},{"key":"2023053018583377000_awac295-B9","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/ng.2653","article-title":"The genotype\u2013Tissue expression (GTEx) project","volume":"45","author":"GTEx Consortium","year":"2013","journal-title":"Nat Genet"},{"key":"2023053018583377000_awac295-B10","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1007\/s11064-010-0318-9","article-title":"Glial cell lines: An overview","volume":"35","author":"De Vries","year":"2010","journal-title":"Neurochem Res"},{"key":"2023053018583377000_awac295-B11","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1002\/jnr.22625","article-title":"Expression of myelin genes: Comparative analysis of Oli-neu and N20.1 oligodendroglial cell lines","volume":"89","author":"Pereira","year":"2011","journal-title":"J Neurosci Res"},{"key":"2023053018583377000_awac295-B12","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1111\/j.1471-4159.2007.04758.x","article-title":"Identification and characterization of SV31, a novel synaptic vesicle membrane protein and potential transporter","volume":"103","author":"Burr\u00e9","year":"2007","journal-title":"J Neurochem"},{"key":"2023053018583377000_awac295-B13","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1111\/tra.12205","article-title":"Cellular zinc levels are modulated by TRPML1-TMEM163 interaction","volume":"15","author":"Cuajungco","year":"2014","journal-title":"Traffic"},{"key":"2023053018583377000_awac295-B14","doi-asserted-by":"crossref","first-page":"11929","DOI":"10.1523\/JNEUROSCI.1860-14.2014","article-title":"An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex","volume":"34","author":"Zhang","year":"2014","journal-title":"J Neurosci"},{"key":"2023053018583377000_awac295-B15","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.neuron.2015.11.013","article-title":"Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse","volume":"89","author":"Zhang","year":"2016","journal-title":"Neuron"},{"key":"2023053018583377000_awac295-B16","doi-asserted-by":"crossref","first-page":"220","DOI":"10.3390\/biomedicines9020220","article-title":"Transmembrane 163 (TMEM163) protein: A new member of the zinc efflux transporter family","volume":"9","author":"Styrpejko","year":"2021","journal-title":"Biomedicines"},{"key":"2023053018583377000_awac295-B17","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1006\/nbdi.1997.0163","article-title":"Zinc metabolism in the brain: Relevance to human neurodegenerative disorders","volume":"4","author":"Cuajungco","year":"1997","journal-title":"Neurobiol Dis"},{"key":"2023053018583377000_awac295-B18","doi-asserted-by":"crossref","first-page":"87","DOI":"10.2174\/1566524043479211","article-title":"Rethinking the excitotoxic ionic milieu: The emerging role of Zn(2+) in ischemic neuronal injury","volume":"4","author":"Sensi","year":"2004","journal-title":"Curr Mol Med"},{"key":"2023053018583377000_awac295-B19","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/0306-4522(88)90312-0","article-title":"Zinc neurotoxicity in cortical cell culture","volume":"24","author":"Choi","year":"1988","journal-title":"Neuroscience"},{"key":"2023053018583377000_awac295-B20","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0304-3940(86)90646-4","article-title":"Brief exposure to zinc is toxic to cortical neurons","volume":"71","author":"Yokoyama","year":"1986","journal-title":"Neurosci Lett"},{"key":"2023053018583377000_awac295-B21","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0074-7742(08)60279-2","article-title":"Neurobiology of zinc and zinc-containing neurons","volume":"31","author":"Frederickson","year":"1989","journal-title":"Int Rev Neurobiol"},{"key":"2023053018583377000_awac295-B22","doi-asserted-by":"crossref","first-page":"134247","DOI":"10.1016\/j.neulet.2019.05.001","article-title":"Zinc homeostasis and zinc signaling in white matter development and injury","volume":"707","author":"Elitt","year":"2019","journal-title":"Neurosci Lett"},{"key":"2023053018583377000_awac295-B23","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1152\/physrev.00035.2014","article-title":"The physiological, biochemical, and molecular roles of zinc transporters in zinc homeostasis and metabolism","volume":"95","author":"Kambe","year":"2015","journal-title":"Physiol Rev"},{"key":"2023053018583377000_awac295-B24","doi-asserted-by":"crossref","DOI":"10.1016\/j.neulet.2021.135944","article-title":"Progress in elucidating pathophysiology of mucolipidosis IV","volume":"755","author":"Misko","year":"2021","journal-title":"Neurosci Lett"},{"key":"2023053018583377000_awac295-B25","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1182\/blood.2020007389","article-title":"A zinc transporter, transmembrane protein 163, is critical for the biogenesis of platelet dense granules","volume":"137","author":"Yuan","year":"2021","journal-title":"Blood"},{"key":"2023053018583377000_awac295-B26","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2020.107704","article-title":"TMEM163 Regulates ATP-gated P2X receptor and behavior","volume":"31","author":"Salm","year":"2020","journal-title":"Cell Rep"},{"key":"2023053018583377000_awac295-B27","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.braindev.2020.06.002","article-title":"A recurrent TMEM106B mutation in hypomyelinating leukodystrophy: A rapid diagnostic assay","volume":"42","author":"Ikemoto","year":"2020","journal-title":"Brain Dev"},{"key":"2023053018583377000_awac295-B28","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1016\/j.ajhg.2019.09.011","article-title":"Heterozygous variants in the mechanosensitive ion channel TMEM63A result in transient hypomyelination during infancy","volume":"105","author":"Yan","year":"2019","journal-title":"Am J Hum Genet"},{"key":"2023053018583377000_awac295-B29","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.braindev.2021.09.006","article-title":"A novel de novo TMEM63A variant in a patient with severe hypomyelination and global developmental delay","volume":"44","author":"Fukumura","year":"2021","journal-title":"Brain Dev"},{"key":"2023053018583377000_awac295-B30","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.3390\/cells11081285","article-title":"Functional study of TMEM163 gene variants associated with hypomyelination leukodystrophy","volume":"11","author":"Yan","year":"2022","journal-title":"Cells"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awac295\/45968675\/awac295.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/145\/12\/4202\/50491324\/awac295.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/145\/12\/4202\/50491324\/awac295.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T14:52:37Z","timestamp":1700923957000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/145\/12\/4202\/6661440"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,12]]},"references-count":30,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,8,12]]},"published-print":{"date-parts":[[2022,12,19]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awac295","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12,1]]},"published":{"date-parts":[[2022,8,12]]}}}