{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T14:25:08Z","timestamp":1792074308737,"version":"4.4.0"},"reference-count":21,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Israel Science Foundation (ISF)","award":["923\/22"],"award-info":[{"award-number":["923\/22"]}]},{"name":"Israel Science Foundation (ISF)","award":["1416\/19"],"award-info":[{"award-number":["1416\/19"]}]},{"name":"Israel Science Foundation (ISF)","award":["2841\/19"],"award-info":[{"award-number":["2841\/19"]}]},{"name":"Israel Science Foundation (ISF)","award":["2023-025I3"],"award-info":[{"award-number":["2023-025I3"]}]},{"DOI":"10.13039\/501100008731","name":"European Leukodystrophy Association (ELA)","doi-asserted-by":"publisher","award":["923\/22"],"award-info":[{"award-number":["923\/22"]}],"id":[{"id":"10.13039\/501100008731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008731","name":"European Leukodystrophy Association (ELA)","doi-asserted-by":"publisher","award":["1416\/19"],"award-info":[{"award-number":["1416\/19"]}],"id":[{"id":"10.13039\/501100008731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008731","name":"European Leukodystrophy Association (ELA)","doi-asserted-by":"publisher","award":["2841\/19"],"award-info":[{"award-number":["2841\/19"]}],"id":[{"id":"10.13039\/501100008731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008731","name":"European Leukodystrophy Association (ELA)","doi-asserted-by":"publisher","award":["2023-025I3"],"award-info":[{"award-number":["2023-025I3"]}],"id":[{"id":"10.13039\/501100008731","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>HIKESHI-related hypomyelinating leukodystrophy (HHL) is a life-threatening disorder caused by homozygous pathogenic variants in HIKESHI. Symptoms include infantile onset progressive spastic dystonic quadriplegia, nystagmus, failure to thrive, diffused hypomyelination, and severe morbidity or death following febrile illness. V54L variants in HIKESHI are particularly prevalent within the Ashkenazi Jewish population. Here, we identified a novel P78S disease-causing variant in HIKESHI in a patient of Christian Arab origin, presenting with clinical and radiologic features characteristic of HHL. In silico analysis suggests that the mutated residue may affect the HIKESHI protein\u2019s dimerization domain. We generated a comprehensive set of induced pluripotent stem cells (iPSCs) from the index case and two additional HHL patients. To investigate mechanisms potentially linked to febrile illness in HHL, we used these cells to study the heat shock (HS) response. HHL-iPSCs showed dramatically decreased levels of HIKESHI compared with healthy controls following HS. In addition, they exhibited increased HSP70 mRNA levels in response to HS, suggesting an increased sensitivity. HHL-iPSCs had impaired HSP70 translocation to the nucleus. Our results provide a human-relevant model for HHL.<\/jats:p>","DOI":"10.3390\/ijms26136037","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T06:49:38Z","timestamp":1750747778000},"page":"6037","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Novel Pathogenic Variant Identified in HIKESHI-Related Hypomyelinating Leukodystrophy Disrupts Heat Shock Response in iPSCs"],"prefix":"10.3390","volume":"26","author":[{"given":"Mahmood Ali","family":"Saleh","sequence":"first","affiliation":[{"name":"The Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"The Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5444-0760","authenticated-orcid":false,"given":"Maria","family":"Boichuck","sequence":"additional","affiliation":[{"name":"The Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7582-0466","authenticated-orcid":false,"given":"Aner","family":"Ottolenghi","sequence":"additional","affiliation":[{"name":"The Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Rabinski","sequence":"additional","affiliation":[{"name":"The Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"The Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9833-1371","authenticated-orcid":false,"given":"Omri","family":"Goldenthal","sequence":"additional","affiliation":[{"name":"The Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"The Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Sevilla","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aviva","family":"Fattal-Valevski","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Institute, Dana-Dwek Children\u2019s Hospital, Tel-Aviv Sourasky Medical Center, Tel-Aviv 6423906, Israel"},{"name":"Faculty of Medicine and health sciences, Tel Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6218-3170","authenticated-orcid":false,"given":"Gali","family":"Heimer","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and health sciences, Tel Aviv University, Tel-Aviv 6997801, Israel"},{"name":"Pediatric Neurology Unit, Safra Children\u2019s Hospital, The Sheba Medical Center, Ramat Gan 5262000, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shay","family":"Ben-Shachar","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and health sciences, Tel Aviv University, Tel-Aviv 6997801, Israel"},{"name":"Clalit Research Institute, Ramat-Gan 5262000, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4706-1949","authenticated-orcid":false,"given":"Stephanie","family":"Libzon","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Institute, Dana-Dwek Children\u2019s Hospital, Tel-Aviv Sourasky Medical Center, Tel-Aviv 6423906, Israel"},{"name":"Faculty of Medicine and health sciences, Tel Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orly","family":"Gershoni-Yahalom","sequence":"additional","affiliation":[{"name":"The Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2477-6519","authenticated-orcid":false,"given":"Anat","family":"Ben-Zvi","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"Department of Life Sciences, Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6543-0296","authenticated-orcid":false,"given":"Raz","family":"Zarivach","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"Department of Life Sciences, Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7923-4613","authenticated-orcid":false,"given":"Ayelet","family":"Zerem","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Institute, Dana-Dwek Children\u2019s Hospital, Tel-Aviv Sourasky Medical Center, Tel-Aviv 6423906, Israel"},{"name":"Faculty of Medicine and health sciences, Tel Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3974-3296","authenticated-orcid":false,"given":"Benyamin","family":"Rosental","sequence":"additional","affiliation":[{"name":"The Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3674-1671","authenticated-orcid":false,"given":"Gad David","family":"Vatine","sequence":"additional","affiliation":[{"name":"The Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"The Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"The Zelman Center of Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1136\/jmedgenet-2015-103232","article-title":"Leukoencephalopathy and early death associated with an Ashkenazi-Jewish founder mutation in the Hikeshi gene","volume":"53","author":"Edvardson","year":"2016","journal-title":"J. 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Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6037\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:57:30Z","timestamp":1760032650000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6037"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,24]]},"references-count":21,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26136037"],"URL":"https:\/\/doi.org\/10.3390\/ijms26136037","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,24]]}}}