{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:29:22Z","timestamp":1790710162487,"version":"4.1.0"},"reference-count":36,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T00:00:00Z","timestamp":1736380800000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["2034\/18"],"award-info":[{"award-number":["2034\/18"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["212625\/Z\/18\/Z"],"award-info":[{"award-number":["212625\/Z\/18\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK135268"],"award-info":[{"award-number":["R01DK135268"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["JIMD Reports"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The tightly\u2010regulated spatial and temporal distribution of zinc ion concentrations within cellular compartments is controlled by two groups of Zn<jats:sup>2+<\/jats:sup> transporters: the 14\u2010member ZIP\/SLC39 family, facilitating Zn<jats:sup>2+<\/jats:sup> influx into the cytoplasm from the extracellular space or intracellular organelles; and the 10\u2010member ZnT\/SLC30 family, mobilizing Zn<jats:sup>2+<\/jats:sup> in the opposite direction. Genetic aberrations in most zinc transporters cause human syndromes. Notably, previous studies demonstrated osteopenia and male\u2010specific cardiac death in mice lacking the ZnT5\/<jats:italic>SLC30A5<\/jats:italic> zinc transporter, and suggested association of two homozygous frameshift <jats:italic>SLC30A5<\/jats:italic> variants with perinatal mortality in humans, due to hydrops fetalis and hypertrophic cardiomyopathy. We set out to decipher the molecular basis of a severe hypotonia syndrome. Combining homozygosity mapping and exome sequencing studies of consanguineous Bedouin kindred, as well as transfection experiments and zinc monitoring in HEK293 cells, we demonstrate that a bi\u2010allelic in\u2010frame 3bp deletion variant in <jats:italic>SLC30A5<\/jats:italic>, deleting isoleucine within the highly conserved cation efflux domain of the encoded ZnT5, results in lower cytosolic zinc concentrations, causing a syndrome of severe non\u2010progressive neonatal axial and limb hypotonia with high\u2010arched palate and respiratory failure. There was no evidence of hydrops fetalis, cardiomyopathy or multi\u2010organ involvement. Affected infants required nasogastric tube or gastrostomy feeding, suffered from various degrees of respiratory compromise and failure to thrive and died in infancy. Thus, a biallelic variant in <jats:italic>SLC30A5<\/jats:italic> (ZnT5), affecting cytosolic zinc concentrations, causes a severe hypotonia syndrome with respiratory insufficiency and failure to thrive, lethal by 1 year of age.<\/jats:p>","DOI":"10.1002\/jmd2.12465","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T10:40:56Z","timestamp":1736419256000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Severe neonatal hypotonia due to <scp><i>SLC30A5<\/i><\/scp> variant affecting function of <scp>ZnT5<\/scp> zinc transporter"],"prefix":"10.1002","volume":"66","author":[{"given":"Vadim","family":"Dolgin","sequence":"first","affiliation":[{"name":"The Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences Ben Gurion University  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Chabosseau","sequence":"additional","affiliation":[{"name":"CRCHUM and Department of Medicine Universit\u00e9 de Montr\u00e9al  Montr\u00e9al QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Bistritzer","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, Division of Pediatrics, Soroka University Medical Center, Faculty of Health Sciences Ben\u2010Gurion University of the Negev  Beer Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Noyman","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, Division of Pediatrics, Soroka University Medical Center, Faculty of Health Sciences Ben\u2010Gurion University of the Negev  Beer Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orna","family":"Staretz\u2010Chacham","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Soroka University Medical Center, Faculty of Health Sciences Ben\u2010Gurion University of the Negev  Beer Sheva Israel"},{"name":"Metabolic Clinic, Division of Pediatrics, Soroka University Medical Center, Faculty of Health Sciences Ben\u2010Gurion University of the Negev  Beer Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ohad","family":"Wormser","sequence":"additional","affiliation":[{"name":"The Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences Ben Gurion University  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noam","family":"Hadar","sequence":"additional","affiliation":[{"name":"The Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences Ben Gurion University  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Eskin\u2010Schwartz","sequence":"additional","affiliation":[{"name":"The Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences Ben Gurion University  Beer\u2010Sheva Israel"},{"name":"Soroka Medical Center Genetics Institute  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibi","family":"Kanengisser\u2010Pines","sequence":"additional","affiliation":[{"name":"Soroka Medical Center Genetics Institute  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginat","family":"Narkis","sequence":"additional","affiliation":[{"name":"Soroka Medical Center Genetics Institute  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramy","family":"Abramsky","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Soroka University Medical Center, Faculty of Health Sciences Ben\u2010Gurion University of the Negev  Beer Sheva Israel"},{"name":"Soroka Medical Center Genetics Institute  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eilon","family":"Shany","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Soroka University Medical Center, Faculty of Health Sciences Ben\u2010Gurion University of the Negev  Beer Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy A.","family":"Rutter","sequence":"additional","affiliation":[{"name":"CRCHUM and Department of Medicine Universit\u00e9 de Montr\u00e9al  Montr\u00e9al QC Canada"},{"name":"Department of Diabetes, Endocrinology and Medicine, Faculty of Medicine Imperial College  London UK"},{"name":"LKC School of Medicine Nanyang Technological College  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyla","family":"Marks","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Soroka University Medical Center, Faculty of Health Sciences Ben\u2010Gurion University of the Negev  Beer Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1430-1296","authenticated-orcid":false,"given":"Ohad S.","family":"Birk","sequence":"additional","affiliation":[{"name":"The Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences Ben Gurion University  Beer\u2010Sheva Israel"},{"name":"Soroka Medical Center Genetics Institute  Beer\u2010Sheva Israel"},{"name":"The Danek Gertner Institute of Human Genetics Sheba Medical Center  Tel\u2010Hashomer Ramat Gan Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100320"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu14122526"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2006.03.005"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-003-1070-7"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.11.002"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M605821200"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.05.001"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2014-102351"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12263-015-0487-x"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng913"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.01.018"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx013"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-014-1617-0"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp369"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005919"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy045"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btm404"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1754"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbs017"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-13-134"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb5004064"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01679-y"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-021-00881-4"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.026435"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38397-6"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002239900597"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2021.01.010"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.6A7032.2006"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.15.1775"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-020-00803-8"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M610535200"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0023878"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M701752200"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M506902200"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102011"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13425"}],"container-title":["JIMD Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jmd2.12465","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T07:43:52Z","timestamp":1738050232000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jmd2.12465"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1]]},"references-count":36,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["10.1002\/jmd2.12465"],"URL":"https:\/\/doi.org\/10.1002\/jmd2.12465","archive":["Portico"],"relation":{},"ISSN":["2192-8312","2192-8312"],"issn-type":[{"value":"2192-8312","type":"print"},{"value":"2192-8312","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1]]},"assertion":[{"value":"2024-11-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e12465"}}