{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T05:10:30Z","timestamp":1746508230575,"version":"3.37.3"},"reference-count":16,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T00:00:00Z","timestamp":1666569600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T00:00:00Z","timestamp":1666569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Spooner Girls Fundation"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Variants in the mitochondrial complex I assembly factor, NUBPL are associated with a rare cause of complex I deficiency mitochondrial disease. Patients affected by complex I deficiency harboring homozygous <jats:italic>NUBPL<\/jats:italic> variants typically have neurological problems including seizures, intellectual disability, and ataxia associated with cerebellar hypoplasia. Thus far only 19 cases have been reported worldwide, and no treatment is available for this rare disease.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>To investigate the pathogenesis of NUBPL-associated complex I deficiency, and for translational studies, we generated a knock-in mouse harboring a patient-specific variant <jats:italic>Nubpl<\/jats:italic> c.311T&gt;C; p. L104P reported in three families.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Similar to <jats:italic>Nubpl<\/jats:italic> global knockout mice, the <jats:italic>Nubpl<\/jats:italic> p. L104P homozygous mice are lethal at embryonic day E10.5, suggesting that the <jats:italic>Nubpl<\/jats:italic> p. L104P variant is likely a hypomorph allele. Given the recent link between Parkinson\u2019s disease and loss-of-function <jats:italic>NUBPL<\/jats:italic> variants, we also explored aging-related behaviors and immunocytochemical changes in <jats:italic>Nubpl<\/jats:italic> hemizygous mice and did not find significant behavioral and pathological changes for alpha-synuclein and oxidative stress markers .<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our data suggest that homozygotes with <jats:italic>Nubpl<\/jats:italic> variants, similar to the null mice, are lethal, and heterozygotes are phenotypically and neuropathologically normal. We propose that a tissue-specific knockout strategy is required to establish a mouse model of <jats:italic>Nubpl<\/jats:italic>-associated complex I deficiency disorder for future mechanistic and translational studies.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-022-02446-y","type":"journal-article","created":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T12:08:27Z","timestamp":1666613307000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Early embryonic lethality in complex I associated p.L104P Nubpl mutant mice"],"prefix":"10.1186","volume":"17","author":[{"given":"Cheng","family":"Cheng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Cleak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather","family":"Cater","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Wells","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rod Carlo","family":"Columbres","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alyaa","family":"Shmara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. 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The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Ethics Committee of UC Irvine.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable. This study did not utilize any human material.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"386"}}