{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T02:44:21Z","timestamp":1774320261929,"version":"3.50.1"},"reference-count":25,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T00:00:00Z","timestamp":1675900800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"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\/501100006245","name":"Ministry of Science and Technology, Israel","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hyperinsulinism\/hyperammonemia (HI\/HA) syndrome has been known to be caused by dominant gain\u2010of\u2010function mutations in <jats:italic>GLUD1<\/jats:italic>, encoding the mitochondrial enzyme glutamate dehydrogenase. Pathogenic <jats:italic>GLUD1<\/jats:italic> mutations enhance enzymatic activity by reducing its sensitivity to allosteric inhibition by GTP. Two recent independent studies showed that a similar HI\/HA phenotype can be caused by biallelic mutations in <jats:italic>SLC25A36,<\/jats:italic> encoding pyrimidine nucleotide carrier 2 (PNC2), a mitochondrial nucleotide carrier that transports pyrimidine and guanine nucleotides across the inner mitochondrial membrane: one study reported a single case caused by a homozygous truncating mutation in <jats:italic>SLC25A36<\/jats:italic> resulting in lack of expression of SLC25A36 in patients' fibroblasts. A second study described two siblings with a splice site mutation in <jats:italic>SLC25A36<\/jats:italic>, causing reduction of mitochondrial GTP content, putatively leading to hyperactivation of glutamate dehydrogenase. In an independent study, through combined linkage analysis and exome sequencing, we demonstrate in four individuals of two Bedouin Israeli related families the same disease\u2010causing <jats:italic>SLC25A36<\/jats:italic> (NM_018155.3) c.284\u2009+\u20093A\u2009&gt;\u2009T homozygous splice\u2010site mutation found in the two siblings. We demonstrate that the mutation, while causing skipping of exon 3, does not abrogate expression of mRNA and protein of the mutant <jats:italic>SLC25A36<\/jats:italic> in patients' blood and fibroblasts. Affected individuals had hyperinsulinism, hyperammonemia, borderline low birth weight, tonic\u2013clonic seizures commencing around 6\u00a0months of age, yet normal intellect and no significant other morbidities. Chronic constipation, hypothyroidism, and developmental delay previously described in a single patient were not found. We thus verify that biallelic <jats:italic>SLC25A36<\/jats:italic> mutations indeed cause HI\/HA syndrome and clearly delineate the disease phenotype.<\/jats:p>","DOI":"10.1002\/jimd.12594","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T13:32:37Z","timestamp":1674653557000},"page":"744-755","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Hyperinsulinism\/hyperammonemia syndrome caused by biallelic <scp><i>SLC25A36<\/i><\/scp> mutation"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7317-3258","authenticated-orcid":false,"given":"Amit","family":"Safran","sequence":"first","affiliation":[{"name":"Morris Kahn Laboratory of Human Genetics at the Shraga Segal Department of Microbiology, Immunology and Genetics Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben Gurion University  Beer Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9263-4905","authenticated-orcid":false,"given":"Regina","family":"Proskorovski\u2010Ohayon","sequence":"additional","affiliation":[{"name":"Morris Kahn Laboratory of Human Genetics at the Shraga Segal Department of Microbiology, Immunology and Genetics Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben Gurion University  Beer Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0507-1505","authenticated-orcid":false,"given":"Marina","family":"Eskin\u2010Schwartz","sequence":"additional","affiliation":[{"name":"Morris Kahn Laboratory of Human Genetics at the Shraga Segal Department of Microbiology, Immunology and Genetics Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben Gurion University  Beer Sheva Israel"},{"name":"Genetics Institute Soroka Medical Center  Beer Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2218-9938","authenticated-orcid":false,"given":"Yuval","family":"Yogev","sequence":"additional","affiliation":[{"name":"Morris Kahn Laboratory of Human Genetics at the Shraga Segal Department of Microbiology, Immunology and Genetics Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben Gurion University  Beer Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0616-6776","authenticated-orcid":false,"given":"Max","family":"Drabkin","sequence":"additional","affiliation":[{"name":"Morris Kahn Laboratory of Human Genetics at the Shraga Segal Department of Microbiology, Immunology and Genetics Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben Gurion University  Beer Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5520-9416","authenticated-orcid":false,"given":"Ekaterina","family":"Eremenko","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Shraga Segal Department of Microbiology, Immunology and Genetics National Institute of Biotechnology in the Negev, Zlotowski Neuroscience Center and the Regenerative Medicine and Stem Cell Research Center, Ben\u2010Gurion University  Beer Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8011-9815","authenticated-orcid":false,"given":"Sarit","family":"Aharoni","sequence":"additional","affiliation":[{"name":"Morris Kahn Laboratory of Human Genetics at the Shraga Segal Department of Microbiology, Immunology and Genetics Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben Gurion University  Beer Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6768-5196","authenticated-orcid":false,"given":"Ofek","family":"Freund","sequence":"additional","affiliation":[{"name":"Morris Kahn Laboratory of Human Genetics at the Shraga Segal Department of Microbiology, Immunology and Genetics Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben Gurion University  Beer Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0653-7573","authenticated-orcid":false,"given":"Matan M.","family":"Jean","sequence":"additional","affiliation":[{"name":"Morris Kahn Laboratory of Human Genetics at the Shraga Segal Department of Microbiology, Immunology and Genetics Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben Gurion University  Beer Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1910-4662","authenticated-orcid":false,"given":"Nadav","family":"Agam","sequence":"additional","affiliation":[{"name":"Morris Kahn Laboratory of Human Genetics at the Shraga Segal Department of Microbiology, Immunology and Genetics Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben Gurion University  Beer Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2483-2090","authenticated-orcid":false,"given":"Noam","family":"Hadar","sequence":"additional","affiliation":[{"name":"Morris Kahn Laboratory of Human Genetics at the Shraga Segal Department of Microbiology, Immunology and Genetics Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben Gurion University  Beer Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7926-0566","authenticated-orcid":false,"given":"Neta","family":"Loewenthal","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Unit, Pediatric Division Soroka Medical Center  Beer Sheva Israel"},{"name":"Faculty of Health Sciences Ben Gurion University  Beer Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6975-4909","authenticated-orcid":false,"given":"Orna","family":"Staretz\u2010Chacham","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences Ben Gurion University  Beer Sheva Israel"},{"name":"Pediatric Metabolic Clinic, Pediatric Division Soroka Medical Center, Ben\u2010Gurion University  Beer Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1430-1296","authenticated-orcid":false,"given":"Ohad S.","family":"Birk","sequence":"additional","affiliation":[{"name":"Morris Kahn Laboratory of Human Genetics at the Shraga Segal Department of Microbiology, Immunology and Genetics Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben Gurion University  Beer Sheva Israel"},{"name":"Genetics Institute Soroka Medical Center  Beer Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,2,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2004.10.040"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469\u20108749.2008.03114.x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11154\u2010010\u20109146\u20100"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1515\/jpem\u20102019\u20100416"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2011.10.015"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE\u201009\u20100615"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00028.2010"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22189929"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab932"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp369"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet\u20102015\u2010103352"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1086\/504158"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003819\u20102"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20084"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00009.2020"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.610808"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00290446"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.543926"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.146"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2012.05.028"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20190057"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2653"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/38.5.747"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2015.09.045"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12594","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jimd.12594","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12594","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T21:03:00Z","timestamp":1692219780000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jimd.12594"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,9]]},"references-count":25,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,7]]}},"alternative-id":["10.1002\/jimd.12594"],"URL":"https:\/\/doi.org\/10.1002\/jimd.12594","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,9]]},"assertion":[{"value":"2022-05-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}