Biallelic germline variants in the hematologic malignancy predisposition gene <i>DDX41</i> cause retinal dystrophy through dysregulation of retinal homeostasis

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 <i>DDX41</i> , 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>C (p. Ile396Thr) and in the retina of <i>Ddx41 <sup>I396T/I396T</sup></i> 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 Müller 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 <i>DDX41</i> in LCA/EOSRD and provide new insights into the role of helicases in retinal homeostasis.

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medRxiv
Published
2026-01-30
DOI
https://doi.org/10.64898/2026.01.28.26344834
Primary Topic
Retinal Development and Disorders
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article
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article

Biallelic germline variants in the hematologic malignancy predisposition gene DDX41 cause retinal dystrophy through dysregulation of retinal homeostasis

Lucas Fares‐Taie, Hafiz Muhammad Jafar Hussain, Jérôme E. Roger, Duanya Liu et al.
medRxiv
Retinal Development and Disorders
article

Biallelic germline variants in the hematologic malignancy predisposition gene DDX41 cause retinal dystrophy through dysregulation of retinal homeostasis

Lucas Fares‐Taie, Hafiz Muhammad Jafar Hussain, Jérôme E. Roger, Duanya Liu, V Michel, Béatrice Bocquet, I. Meunier, Pierre David, Isabelle Perrault, Karolina Kamińska, Line Kessel, Paul Yang, Takero Miyagawa, Sebastian M. Fica, I. Audo, H. Dollfus, K. Wadt, Matthieu P. Robert, Vincent Jung, Abigail R. Moye, Ewa Matczyńska, Pilar Barberán-Martínez, Andrea Zanetti, Stéphane Giraudier, Christina Zeitz, Aline Antonio, F. Rieux-Laucat, Carlo Rivolta, Siying Lin, Gavin Arno, Xuan Bao, Olivier PATAT, Meng Wang, Mark E. Pennesi, Slawomir Teper, Chiara Ida Guerrera, Anna Boguszewska-Chachulska, Carmen Ayuso, Rui Sousa-Luis, Li Yumei, Rui Chen, Jean-Michel Rozet, Zoeline Mars, Jose M. Millan, M Pilar Martin-Gutierrez, Louise Gioja, Marie Sebert, Christel Condroyer, Andrew R. Webster
article en

Abstract

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 <i>DDX41</i> , 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>C (p. Ile396Thr) and in the retina of <i>Ddx41 <sup>I396T/I396T</sup></i> 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 Müller 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 <i>DDX41</i> in LCA/EOSRD and provide new insights into the role of helicases in retinal homeostasis.

medRxiv
University of Copenhagen (DK), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Moorfields Eye Hospital NHS Foundation Trust (GB), Institut de la Vision (FR), Transgene (France) (FR), University of Leicester (GB), Inserm (FR), Oregon Health & Science University (US), Medical University of Silesia (PL), Baylor College of Medicine (US), University of Basel (CH), Université de Montpellier (FR), University of California, Irvine (US), Université Paris Cité (FR), Université Paris-Saclay (FR), Centre hospitalier national d'ophtalmologie des Quinze-Vingts (FR), Glostrup Hospital (DK), University Hospital of Basel (CH), Copenhagen University Hospital (DK), Rigshospitalet (DK), University of Manchester (GB), Hospital Universitari i Politècnic La Fe (ES), Centre Hospitalier Universitaire de Toulouse (FR), Sorbonne Université (FR), University of Oxford (GB), Institut Necker Enfants Malades (FR), Institut des Neurosciences Paris-Saclay (FR), Sorbonne Paris Cité (FR), Manchester University NHS Foundation Trust (GB), Centre Hospitalier Universitaire de Montpellier (FR), Assistance Publique – Hôpitaux de Paris (FR), St Mary's Hospital (GB), Centre for Biomedical Network Research on Rare Diseases (ES), Retina Foundation of the Southwest (US), Department of Biomedicine Basel (CH), Hospital Universitario Fundación Jiménez Díaz (ES), Institute of Ophthalmology (MX), Institute for Neurosciences of Montpellier (FR), Institut Cochin (FR), Hôpital Saint-Louis (FR), Hôpitaux Universitaires de Strasbourg (FR), Genomed (Poland) (PL), Greenwood Genetic Center (US), Institut des Maladies Génétiques Imagine (FR), Institute of Molecular and Clinical Ophthalmology Basel (CH), Instituto de Investigación Sanitaria La Fe (ES), Structure fédérative de recherche Necker (FR), University College London (GB), Universidad Autónoma de Madrid (ES), Université de Strasbourg (FR), University of Silesia in Katowice (PL)
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