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Using\n                    <jats:italic>in vivo<\/jats:italic>\n                    genetic engineering to study disturbed GLE1 functions under physiological conditions, we demonstrate that total inactivation of GLE1 results in disorganization of the blastocyst inner cell mass and early embryonic lethality due to defects in lineage specification. In contrast, the knock\u2010in mice genocopying the LCCS1\u2010associated\n                    <jats:italic>GLE1<\/jats:italic>\n                    <jats:sub>FinMajor<\/jats:sub>\n                    variant (\n                    <jats:italic>Gle1<\/jats:italic>\n                    <jats:sup>PFQ\/PFQ<\/jats:sup>\n                    ) survive the prenatal period but die suddenly at midadulthood.\n                    <jats:italic>Gle1<\/jats:italic>\n                    <jats:sup>PFQ\/PFQ<\/jats:sup>\n                    mice present an irregular count and distribution of spinal motor neurons as well as impaired development of neural crest\u2010derived tissues, as demonstrated by defects in the sympathetic innervation of heart ventricles, irregularities in the paravertebral sympathetic ganglia volume, and decreased adrenal chromaffin cell counts. Unlike previously reported for yeast and HeLa cells, analysis of the molecular consequences of the\n                    <jats:italic>GLE1<\/jats:italic>\n                    <jats:sub>FinMajor<\/jats:sub>\n                    variant identified normal poly(A)\u2009+\u2009RNA distribution in\n                    <jats:italic>Gle1<\/jats:italic>\n                    <jats:sup>PFQ\/PFQ<\/jats:sup>\n                    cells; however, cells were impaired in RNA and protein synthesis and simultaneously showed severely disturbed formation of G3BP stress granule assembly factor 1 (G3BP1)\u2010positive stress granules. Intriguingly, stressed\n                    <jats:italic>Gle1<\/jats:italic>\n                    <jats:sup>PFQ\/PFQ<\/jats:sup>\n                    cells show microRNA profiles indicative of impaired transcription, protein metabolism, nervous system development, and axon guidance, further corroborating our functional findings. Our results show the necessity of functional GLE1 for life and indicate that LCCS1 etiology is a result of the pathogenic\n                    <jats:italic>GLE1<\/jats:italic>\n                    <jats:sub>FinMajor<\/jats:sub>\n                    variant impinging differentiation of neural crest derivatives and leading to complex multiorgan defects.\n                  <\/jats:p>","DOI":"10.1111\/febs.70195","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T16:55:41Z","timestamp":1752771341000},"page":"6365-6399","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>In vivo<\/i>\n                    modeling of lethal congenital contracture syndrome 1 suggests pathomechanisms in cellular stress responses"],"prefix":"10.1111","volume":"292","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6402-9708","authenticated-orcid":false,"given":"Tom\u00e1\u0161","family":"Z\u00e1rybnick\u00fd","sequence":"first","affiliation":[{"name":"Helsinki Institute of Life Science University of Helsinki  Finland"},{"name":"Stem Cells and Metabolism Research Program Unit, Faculty of Medicine University of Helsinki  Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonja","family":"Lindfors","sequence":"additional","affiliation":[{"name":"Helsinki Institute of Life Science University of Helsinki  Finland"},{"name":"Stem Cells and Metabolism Research Program Unit, Faculty of Medicine University of Helsinki  Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saana","family":"Metso","sequence":"additional","affiliation":[{"name":"Helsinki Institute of Life Science University of Helsinki  Finland"},{"name":"Stem Cells and Metabolism Research Program Unit, Faculty of Medicine University of Helsinki  Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Koivula","sequence":"additional","affiliation":[{"name":"Helsinki Institute of Life Science University of Helsinki  Finland"},{"name":"Stem Cells and Metabolism Research Program Unit, Faculty of Medicine University of Helsinki  Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zoltan","family":"Szabo","sequence":"additional","affiliation":[{"name":"Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology University of Oulu  Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rasmus","family":"Valtonen","sequence":"additional","affiliation":[{"name":"Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology University of Oulu  Finland"},{"name":"Medical Research Center Oulu Oulu University Hospital and University of Oulu  Finland"},{"name":"Biocenter Oulu University of Oulu  Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikko","family":"Tulppo","sequence":"additional","affiliation":[{"name":"Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology University of Oulu  Finland"},{"name":"Biocenter Oulu University of Oulu  Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4688-9098","authenticated-orcid":false,"given":"Johanna","family":"Magga","sequence":"additional","affiliation":[{"name":"Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology University of Oulu  Finland"},{"name":"Biocenter Oulu University of Oulu  Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samu","family":"Saarim\u00e4ki","sequence":"additional","affiliation":[{"name":"Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology University of Oulu  Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonja","family":"Bl\u00e4uer","sequence":"additional","affiliation":[{"name":"Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology University of Oulu  Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilkka","family":"Miinalainen","sequence":"additional","affiliation":[{"name":"Biocenter Oulu University of Oulu  Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Risto","family":"Kerkel\u00e4","sequence":"additional","affiliation":[{"name":"Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology University of Oulu  Finland"},{"name":"Medical Research Center Oulu Oulu University Hospital and University of Oulu  Finland"},{"name":"Biocenter Oulu University of Oulu  Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petteri. 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