{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T11:02:34Z","timestamp":1775991754242,"version":"3.50.1"},"posted":{"date-parts":[[2025,6,15]]},"group-title":"Cell Biology","reference-count":43,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,15]],"date-time":"2025-06-15T00:00:00Z","timestamp":1749945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Endoplasmic reticulum (ER)-associated degradation (ERAD) is essential for cellular proteostasis, with the SEL1L-HRD1 protein complex targeting misfolded proteins in the ER for proteasomal degradation. Disruption of this pathway underlies a recently identified infant-onset neurodevelopmental disorder (ENDI syndrome), characterized by profound developmental delay, microcephaly, and immune deficiency. Its most severe form, ENDI with agammaglobulinemia (ENDI-A), is driven by a bi-allelic SEL1L Cys141Tyr (C141Y) mutation within the fibronectin II (FNII) domain, for which no treatment currently exists. Here, we serendipitously uncover a striking mechanism of intrinsic rescue in knock-in mouse models of the C141Y mutation: enhanced usage of an alternative splice donor site within exon 4 bypasses the mutant FNII-encoding region, restoring ERAD activity and rescuing key disease phenotypes including perinatal lethality, growth retardation, B cell deficiency, and neurodevelopmental defects. Building on this discovery, we demonstrate that antisense oligonucleotide (ASO)-mediated exon skipping in patient-derived fibroblasts generates a truncated yet functional SEL1L protein, fully rescuing ERAD function and ER proteostasis. These results establish RNA splicing modulation as a viable therapeutic strategy for ERAD deficiency and extend the clinical potential of exon-skipping therapy to diseases of protein misfolding.<\/jats:p>\n                <jats:sec>\n                  <jats:title>ONE-SENTENCE SUMMARY<\/jats:title>\n                  <jats:p>This study reports the discovery of using antisense oligonucleotides (ASOs) to rescue the biallelic SEL1L C141Y variant, offering a potential therapeutic strategy.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.06.13.659581","type":"posted-content","created":{"date-parts":[[2025,6,15]],"date-time":"2025-06-15T19:05:13Z","timestamp":1750014313000},"source":"Crossref","is-referenced-by-count":0,"title":["Functional rescue of a fatal ERAD mutation via alternative splicing"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0583-1386","authenticated-orcid":false,"given":"Huilun Helen","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liangguang Leo","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunil K","family":"Verma","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weronika","family":"Gniadzik","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine, Charlottesville, VA 22908, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zexin Jason","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lulu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine, Charlottesville, VA 22908, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muge N","family":"Kuyumcu-Martinez","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA"},{"name":"Robert M. 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