{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:06:39Z","timestamp":1790762799636,"version":"4.1.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T00:00:00Z","timestamp":1611100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL) is a leukodystrophy caused by missense mutations of the aspartyl-tRNA synthetase-encoding gene <jats:italic>DARS1<\/jats:italic>. The clinical picture includes the regression of acquired motor milestones, spasticity, ataxia, seizures, nystagmus, and intellectual disabilities. Morphologically, HBSL is characterized by a distinct pattern of hypomyelination in the central nervous system including the anterior brainstem, the cerebellar peduncles and the supratentorial white matter as well as the dorsal columns and the lateral corticospinal tracts of the spinal cord. Adequate HBSL animal models are lacking. <jats:italic>Dars1<\/jats:italic> knockout mice are embryonic lethal precluding examination of the etiology. To address this, we introduced the HBSL-causing <jats:italic>Dars1<\/jats:italic><jats:sup><jats:italic>D<\/jats:italic>367<jats:italic>Y<\/jats:italic><\/jats:sup> point mutation into the mouse genome. Surprisingly, mice carrying this mutation homozygously were phenotypically normal. As hypomorphic mutations are more severe in trans to a deletion, we crossed <jats:italic>Dars1<\/jats:italic><jats:sup><jats:italic>D<\/jats:italic>367<jats:italic>Y<\/jats:italic>\/<jats:italic>D<\/jats:italic>367<jats:italic>Y<\/jats:italic><\/jats:sup> mice with <jats:italic>Dars1-null<\/jats:italic> carriers. The resulting <jats:italic>Dars1<\/jats:italic><jats:sup><jats:italic>D<\/jats:italic>367<jats:italic>Y<\/jats:italic>\/\u2212<\/jats:sup> offspring displayed a strong developmental delay compared to control <jats:italic>Dars1<\/jats:italic><jats:sup><jats:italic>D<\/jats:italic>367<jats:italic>Y<\/jats:italic>\/+<\/jats:sup> littermates, starting during embryogenesis. Only a small fraction of <jats:italic>Dars1<\/jats:italic><jats:sup><jats:italic>D<\/jats:italic>367<jats:italic>Y<\/jats:italic>\/\u2212<\/jats:sup> mice were born, and half of these mice died with hydrocephalus during the first 3 weeks of life. Of the few <jats:italic>Dars1<\/jats:italic><jats:sup><jats:italic>D<\/jats:italic>367<jats:italic>Y<\/jats:italic>\/\u2212<\/jats:sup> mice that were born at term, 25% displayed microphthalmia. Throughout postnatal life, <jats:italic>Dars1<\/jats:italic><jats:sup><jats:italic>D<\/jats:italic>367<jats:italic>Y<\/jats:italic>\/\u2212<\/jats:sup> mice remained smaller and lighter than their <jats:italic>Dars1<\/jats:italic><jats:sup><jats:italic>D<\/jats:italic>367<jats:italic>Y<\/jats:italic>\/+<\/jats:sup> littermates. Despite this early developmental deficit, once they made it through early adolescence <jats:italic>Dars1<\/jats:italic><jats:sup><jats:italic>D<\/jats:italic>367<jats:italic>Y<\/jats:italic>\/\u2212<\/jats:sup> mice were phenotypically inconspicuous for most of their adult life, until they developed late onset motor deficits as well as vacuolization and demyelination of the spinal cord white matter. Expression levels of the major myelin proteins were reduced in <jats:italic>Dars1<\/jats:italic><jats:sup><jats:italic>D<\/jats:italic>367<jats:italic>Y<\/jats:italic>\/\u2212<\/jats:sup> mice compared to controls. Taken together, <jats:italic>Dars1<\/jats:italic><jats:sup><jats:italic>D<\/jats:italic>367<jats:italic>Y<\/jats:italic>\/\u2212<\/jats:sup> mice model aspects of the clinical picture of the corresponding missense mutation in HBSL. This model will enable studies of late onset deficits, which is precluded in <jats:italic>Dars1<\/jats:italic> knockout mice, and can be leveraged to test potential HBSL therapeutics including <jats:italic>DARS1<\/jats:italic> gene replacement therapy.<\/jats:p>","DOI":"10.3389\/fncel.2020.625879","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T06:52:08Z","timestamp":1611125528000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["A Hypomorphic Dars1D367Y Model Recapitulates Key Aspects of the Leukodystrophy HBSL"],"prefix":"10.3389","volume":"14","author":[{"given":"Dominik","family":"Fr\u00f6hlich","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa I.","family":"Mendes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Kueh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"Bongers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco J.","family":"Herold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gajja S.","family":"Salomons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary D.","family":"Housley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Klugmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4181","DOI":"10.1093\/hmg\/ddx307","article-title":"DARS2 protects against neuroinflammation and apoptotic neuronal loss, but is dispensable for myelin producing cells","volume":"26","author":"Aradjanski","year":"2017","journal-title":"Hum. 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