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HBSL is a spectrum disorder with disease onset usually during early childhood and no available treatment options. Patients display regression of previously acquired motor milestones, spasticity, ataxia, seizures, nystagmus, and intellectual disabilities. Gene-function studies in mice revealed that homozygous\n                    <jats:italic>Dars1<\/jats:italic>\n                    deletion is embryonically lethal, suggesting that successful modelling of HBSL requires the generation of disease-causing genocopies in mice. In this study, we introduced the pathogenic\n                    <jats:italic>DARS1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>M256L<\/jats:italic>\n                    <\/jats:sup>\n                    mutation located on exon nine of the murine\n                    <jats:italic>Dars1<\/jats:italic>\n                    locus. Despite causing severe illness in humans, homozygous\n                    <jats:italic>Dars1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>M256L<\/jats:italic>\n                    <\/jats:sup>\n                    mice were only mildly affected. To exacerbate HBSL symptoms, we bred\n                    <jats:italic>Dars1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>M256L<\/jats:italic>\n                    <\/jats:sup>\n                    mice with\n                    <jats:italic>Dars1<\/jats:italic>\n                    -null \u2018enhancer\u2019 mice. The\n                    <jats:italic>Dars1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>M256L\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    offspring displayed increased embryonic lethality, severe developmental delay, reduced body weight and size, hydrocephalus, anophthalmia, and vacuolization of the white matter. Remarkably, the\n                    <jats:italic>Dars1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>M256L\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    genotype affected energy metabolism and peripheral organs more profoundly than the nervous system and resulted in reduced body fat, increased respiratory exchange ratio, reduced liver steatosis, and reduced hypocellularity of the bone marrow. In summary, homozygous\n                    <jats:italic>Dars1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>M256L<\/jats:italic>\n                    <\/jats:sup>\n                    and compound heterozygous\n                    <jats:italic>Dars1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>M256L\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mutation genotypes recapitulate some aspects of HBSL and primarily manifest in developmental delay as well as metabolic and peripheral changes. These aspects of the disease might have been overlooked in HBSL patients with severe neurological deficits but could be included in the differential diagnosis of HBSL in the future.\n                  <\/jats:p>","DOI":"10.1007\/s11064-022-03582-4","type":"journal-article","created":{"date-parts":[[2022,3,31]],"date-time":"2022-03-31T02:06:43Z","timestamp":1648692403000},"page":"1972-1984","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Developmental delay and late onset HBSL pathology in hypomorphic Dars1M256L mice"],"prefix":"10.1007","volume":"47","author":[{"given":"Matthias","family":"Klugmann","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Kalotay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabien","family":"Delerue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars M.","family":"Ittner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andre","family":"Bongers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josephine","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret J.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary D.","family":"Housley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9551-3620","authenticated-orcid":false,"given":"Dominik","family":"Fr\u00f6hlich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,3,31]]},"reference":[{"key":"3582_CR1","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1016\/j.ajhg.2013.04.006","volume":"92","author":"RJ Taft","year":"2013","unstructured":"Taft RJ, Vanderver A, Leventer RJ, Damiani SA, Simons C, Grimmond SM, Miller D, Schmidt J, Lockhart PJ, Pope K, Ru K, Crawford J, Rosser T, de Coo IF, Juneja M, Verma IC, Prabhakar P, Blaser S, Raiman J, Pouwels PJ, Bevova MR, Abbink TE, van der Knaap MS, Wolf NI (2013) Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity. 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