USH2A variants causing retinitis pigmentosa or Usher syndrome provoke differential retinal phenotypes in disease-specific organoids
Carla Sanjurjo-Soriano,
Carla Jimenez-Medina,
Nejla Erkilic,
Luisina Cappellino,
Arnaud Lefevre,
Kerstin Nagel-Wolfrum,
Uwe Wolfrum,
Erwin Van Wijk,
Anne-Françoise Roux,
Isabelle Meunier,
Vasiliki Kalatzis
Affiliations
Carla Sanjurjo-Soriano
Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France
Carla Jimenez-Medina
Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France
Nejla Erkilic
Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France
Luisina Cappellino
Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France
Arnaud Lefevre
National Reference Centre for Inherited Sensory Diseases, University of Montpellier, CHU, Montpellier, France
Kerstin Nagel-Wolfrum
Institute of Molecular Physiology, Molecular Cell Biology, and Photoreceptor Cell Biology, Johannes Gutenberg University Mainz, Mainz, Germany; Institute of Developmental Biology and Neurobiology, Johannes Gutenberg University Mainz, Mainz, Germany
Uwe Wolfrum
Institute of Molecular Physiology, Molecular Cell Biology, and Photoreceptor Cell Biology, Johannes Gutenberg University Mainz, Mainz, Germany
Erwin Van Wijk
Department of Otorhinolaryngology, Hearing, & Genes, Radboud University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands
Anne-Françoise Roux
Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France; Molecular Genetics Laboratory, University of Montpellier, CHU, Montpellier, France
Isabelle Meunier
Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France; National Reference Centre for Inherited Sensory Diseases, University of Montpellier, CHU, Montpellier, France
Vasiliki Kalatzis
Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France; Corresponding author
Summary: There is an emblematic clinical and genetic heterogeneity associated with inherited retinal diseases (IRDs). The most common form is retinitis pigmentosa (RP), a rod-cone dystrophy caused by pathogenic variants in over 80 different genes. Further complexifying diagnosis, different variants in individual RP genes can also alter the clinical phenotype. USH2A is the most prevalent gene for autosomal-recessive RP and one of the most challenging because of its large size and, hence, large number of variants. Moreover, USH2A variants give rise to non-syndromic and syndromic RP, known as Usher syndrome (USH) type 2, which is associated with vision and hearing loss. The lack of a clear genotype-phenotype correlation or prognostic models renders diagnosis highly challenging. We report here a long-awaited differential non-syndromic RP and USH phenotype in three human disease-specific models: fibroblasts, induced pluripotent stem cells (iPSCs), and mature iPSC-derived retinal organoids. Moreover, we identified distinct retinal phenotypes in organoids from multiple RP and USH individuals, which were validated by isogenic-corrected controls. Non-syndromic RP organoids showed compromised photoreceptor differentiation, whereas USH organoids showed a striking and unexpected cone phenotype. Furthermore, complementary clinical investigations identified macular atrophy in a high proportion of USH compared with RP individuals, further validating our observations that USH2A variants differentially affect cones. Overall, identification of distinct non-syndromic RP and USH phenotypes in multiple models provides valuable and robust readouts for testing the pathogenicity of USH2A variants as well as the efficacy of therapeutic approaches in complementary cell types.
