2. Academic Validation
  3. Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement

Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement

  • Am J Hum Genet. 2020 Jun 4;106(6):859-871. doi: 10.1016/j.ajhg.2020.04.018.
Sabrina Mechaussier 1,  Basamat Almoallem 2,  Christina Zeitz 3,  Kristof Van Schil 4,  Laila Jeddawi 5,  Jo Van Dorpe 6,  Alfredo Dueñas Rey 4,  Christel Condroyer 3,  Olivier Pelle 7,  Michel Polak 8,  Nathalie Boddaert 9,  Nadia Bahi-Buisson 10,  Mara Cavallin 11,  Jean-Louis Bacquet 12,  Alexandra Mouallem-Bézière 12,  Olivia Zambrowski 13,  José Alain Sahel 14,  Isabelle Audo 15,  Josseline Kaplan 16,  Jean-Michel Rozet 1,  Elfride De Baere 17,  Isabelle Perrault 18
Affiliations

Affiliations

  • 1 Laboratory of Genetics in Ophthalmology, INSERM UMR 1163, Institute of Genetic Diseases, Imagine and Paris University, 75015 Paris, France.
  • 2 Center for Medical Genetics and Department of Biomolecular Medicine, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium; Department of Ophthalmology, King Abdul-Aziz University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • 3 Sorbonne Université, INSERM, Centre National de la Recherche Scientifique, Institut de la Vision, 75012 Paris, France.
  • 4 Center for Medical Genetics and Department of Biomolecular Medicine, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium.
  • 5 Pediatric Ophthalmology Division, Dhahran Eye Specialist Hospital, Dhahran 34257, Saudi Arabia.
  • 6 Department of Pathology, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium.
  • 7 Cell Sorting Facility, INSERM UMR 1163, Institute of Genetic Diseases, Imagine and Paris University, 75015 Paris, France.
  • 8 Endocrinology, Gynecology, and Pediatric Diabetology Department, University Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
  • 9 Department of Pediatric Radiology, University Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
  • 10 Pediatric Neurology Department, University Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
  • 11 Laboratory of Embryology and Genetics of Human Malformation, INSERM UMR 1163, Institute of Genetic Diseases, Imagine and Paris University, 75015 Paris, France.
  • 12 Service d'Ophtalmologie, Centre Hospitalier Intercommunal de Créteil, Assistance Publique-Hôpitaux de Paris, 94000 Créteil, France.
  • 13 Service d'Ophtalmologie, Centre Hospitalier Intercommunal de Créteil, Assistance Publique-Hôpitaux de Paris, 94000 Créteil, France; Ophthalmology Department, University Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
  • 14 Sorbonne Université, INSERM, Centre National de la Recherche Scientifique, Institut de la Vision, 75012 Paris, France; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM, Direction de l'Hospitalisation et de l'Organisation des Soins (DHOS), Centres d'Investigations Cliniques (CIC) 1423, 75012 Paris, France; Fondation Ophtalmologique Adolphe de Rothschild, 75019 Paris, France; Académie des Sciences, Institut de France, 75006 Paris, France; Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, PA 15213, USA.
  • 15 Sorbonne Université, INSERM, Centre National de la Recherche Scientifique, Institut de la Vision, 75012 Paris, France; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM, Direction de l'Hospitalisation et de l'Organisation des Soins (DHOS), Centres d'Investigations Cliniques (CIC) 1423, 75012 Paris, France; Institute of Ophthalmology, University College of London, London EC1V 9EL, UK.
  • 16 Laboratory of Genetics in Ophthalmology, INSERM UMR 1163, Institute of Genetic Diseases, Imagine and Paris University, 75015 Paris, France; Service d'Ophtalmologie, Centre Hospitalier Intercommunal de Créteil, Assistance Publique-Hôpitaux de Paris, 94000 Créteil, France.
  • 17 Center for Medical Genetics and Department of Biomolecular Medicine, Ghent University and Ghent University Hospital, 9000 Ghent, Belgium. Electronic address: elfride.debaere@ugent.be.
  • 18 Laboratory of Genetics in Ophthalmology, INSERM UMR 1163, Institute of Genetic Diseases, Imagine and Paris University, 75015 Paris, France. Electronic address: isabelle.perrault@inserm.fr.
PMID: 32470375 DOI: 10.1016/j.ajhg.2020.04.018
Abstract

Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. RIMS2 regulates synaptic membrane exocytosis. Data mining of human adult bulk and single-cell retinal transcriptional datasets revealed predominant expression in rod photoreceptors, and immunostaining demonstrated RIMS2 localization in the human retinal outer plexiform layer, Purkinje cells, and pancreatic islets. Additionally, nonsense variants were shown to result in truncated RIMS2 and decreased Insulin secretion in mammalian cells. The identification of a syndromic stationary congenital IRD has a major impact on the differential diagnosis of syndromic congenital IRD, which has previously been exclusively linked with degenerative IRD.

Keywords

CRSD; RIMS2; congenital cone-rod synaptic disorder; differential diagnosis; exome sequencing; neurodevelopmental or pancreatic involvement; stationary versus degenerative retinal disease; synaptic membrane exocytosis gene; syndromic.

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