{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:10:50Z","timestamp":1790647850034,"version":"4.1.0"},"posted":{"date-parts":[[2026,1,30]]},"group-title":"Genetic and Genomic Medicine","reference-count":72,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Leber congenital amaurosis (LCA) and Early-onset severe retinal dystrophy (EOSRD) manifest within the first months and the first years of life, respectively. They are the leading cause of severe vision impairment in childhood. Using next generation sequencing, we identified eight families of patients with LCA\/EOSRD carrying biallelic combination of six germline variants in\n                  <jats:italic>DDX41<\/jats:italic>\n                  , encoding a DEAD-box ATPase RNA helicase involved in RNA splicing, innate immunity and hematopoiesis. In fibroblasts from a patient carrying the homozygous missense variant c.1187T&gt;C (p. Ile396Thr) and in the retina of\n                  <jats:italic>\n                    Ddx41\n                    <jats:sup>I396T\/I396T<\/jats:sup>\n                  <\/jats:italic>\n                  mice, DDX41 protein expression was decreased. Electroretinogram recordings in these animals also revealed significant visual dysfunction since the first month of age, supporting a pathogenic role of DDX41 in retinal physiology. Immunohistochemical staining showed that the protein localized to nuclei in all major retinal cell types and to photoreceptor synapses, while biochemical assays showed that LCA\/EOSRD variants disrupt DDX41 interactions with RNA through misfolding or the formation of non-productive aggregates, resulting in loss-of-function. Transcriptomic profiling of mutant mouse retinas revealed dysregulation of gene networks associated with M\u00fcller cells (MCs), glial cells essential for maintaining retinal structure, metabolic balance, and immune surveillance. The dysregulated pathways chiefly involved cell morphogenesis and junction formation, consistent with immunohistological analyses of widespread architectural disruption and nuclear disorganization, identifying MCs as a site of dysfunction. Together, these findings establish for the first time the involvement of\n                  <jats:italic>DDX41<\/jats:italic>\n                  in LCA\/EOSRD and provide new insights into the role of helicases in retinal homeostasis.\n                <\/jats:p>","DOI":"10.64898\/2026.01.28.26344834","type":"posted-content","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T22:25:17Z","timestamp":1769811917000},"source":"Crossref","is-referenced-by-count":2,"title":["Biallelic germline variants in the hematologic malignancy predisposition gene\n                  <i>DDX41<\/i>\n                  cause retinal dystrophy through dysregulation of retinal homeostasis"],"prefix":"10.64898","author":[{"given":"Zo\u00e9line","family":"Mars","sequence":"first","affiliation":[{"name":"Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institut Imagine and Paris Cit\u00e9 University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Zanetti","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institut Imagine and Paris Cit\u00e9 University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"Kaminska","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, 4031, Switzerland,"},{"name":"Department of Ophthalmology, University of Basel, Basel, 4031, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takero","family":"Miyagawa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duanya","family":"Liu","sequence":"additional","affiliation":[{"name":"Institut de Recherche Saint-Louis, INSERM UMRS 1131, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline","family":"Antonio","sequence":"additional","affiliation":[{"name":"Institut de la Vision, Sorbonne Universit\u00e9, INSERM, CNRS, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Arno","sequence":"additional","affiliation":[{"name":"NIHR Biomedical Research Centre, Moorfields Eye Hospital and the UCL Institute of Ophthalmology, London, EC1V 9EL, UK"},{"name":"UCL Institute of Ophthalmology, University College London, London, EC1V 9EL, UK,"},{"name":"Division of Research, Greenwood Genetic Center, Greenwood, South Carolina, 29646, USA,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0698-5309","authenticated-orcid":false,"given":"Isabelle","family":"Audo","sequence":"additional","affiliation":[{"name":"Institut de la Vision, Sorbonne Universit\u00e9, INSERM, CNRS, Paris, 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