例如:"lncRNA", "apoptosis", "WRKY"

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders.

Hum. Mutat.2019 Jun;40(6):765-787. doi:10.1002/humu.23735. Epub 2019 Mar 28
Christina Zeitz 1 , Christelle Michiels 1 , Marion Neuillé 1 , Christoph Friedburg 2 , Christel Condroyer 1 , Fiona Boyard 1 , Aline Antonio 3 , Nassima Bouzidi 1 , Diana Milicevic 1 , Robin Veaux 1 , Aurore Tourville 1 , Axelle Zoumba 1 , Imene Seneina 1 , Marine Foussard 1 , Camille Andrieu 3 , Markus N Preising 2 , Steven Blanchard 4 , Jean-Paul Saraiva 4 , Lilia Mesrob 5 , Edith Le Floch 6 , Claire Jubin 6 , Vincent Meyer 6 , Hélène Blanché 7 , Anne Boland 6 , Jean-François Deleuze 7 , Dror Sharon 8 , Isabelle Drumare 9 , Sabine Defoort-Dhellemmes 9 , Elfride De Baere 10 , Bart P Leroy 11 , Xavier Zanlonghi 12 , Ingele Casteels 13 , Thomy J de Ravel 14 , Irina Balikova 15 , Rob K Koenekoop 16 , Fanny Laffargue 17 , Rebecca McLean 18 , Irene Gottlob 18 , Dominique Bonneau 19 , Daniel F Schorderet 20 , Francis L Munier 21 , Martin McKibbin 22 , Katrina Prescott 23 , Valerie Pelletier 24 , Hélène Dollfus 25 , Yaumara Perdomo-Trujillo 26 , Céline Faure 27 , Charlotte Reiff 28 , Bernd Wissinger 29 , Isabelle Meunier 30 , Susanne Kohl 29 , Eyal Banin 8 , Eberhart Zrenner 31 , Bernhard Jurklies 32 , Birgit Lorenz 2 , José-Alain Sahel 33 , Isabelle Audo 34
Christina Zeitz 1 , Christelle Michiels 1 , Marion Neuillé 1 , Christoph Friedburg 2 , Christel Condroyer 1 , Fiona Boyard 1 , Aline Antonio 3 , Nassima Bouzidi 1 , Diana Milicevic 1 , Robin Veaux 1 , Aurore Tourville 1 , Axelle Zoumba 1 , Imene Seneina 1 , Marine Foussard 1 , Camille Andrieu 3 , Markus N Preising 2 , Steven Blanchard 4 , Jean-Paul Saraiva 4 , Lilia Mesrob 5 , Edith Le Floch 6 , Claire Jubin 6 , Vincent Meyer 6 , Hélène Blanché 7 , Anne Boland 6 , Jean-François Deleuze 7 , Dror Sharon 8 , Isabelle Drumare 9 , Sabine Defoort-Dhellemmes 9 , Elfride De Baere 10 , Bart P Leroy 11 , Xavier Zanlonghi 12 , Ingele Casteels 13 , Thomy J de Ravel 14 , Irina Balikova 15 , Rob K Koenekoop 16 , Fanny Laffargue 17 , Rebecca McLean 18 , Irene Gottlob 18 , Dominique Bonneau 19 , Daniel F Schorderet 20 , Francis L Munier 21 , Martin McKibbin 22 , Katrina Prescott 23 , Valerie Pelletier 24 , Hélène Dollfus 25 , Yaumara Perdomo-Trujillo 26 , Céline Faure 27 , Charlotte Reiff 28 , Bernd Wissinger 29 , Isabelle Meunier 30 , Susanne Kohl 29 , Eyal Banin 8 , Eberhart Zrenner 31 , Bernhard Jurklies 32 , Birgit Lorenz 2 , José-Alain Sahel 33 , Isabelle Audo 34
+ et al

[No authors listed]

Author information
  • 1 INSERM, CNRS, Institut de la Vision, Sorbonne Université, Paris, France.
  • 2 Department of Ophthalmology, Justus-Liebig-University Giessen, Germany.
  • 3 CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DGOS CIC 1423, Paris, France.
  • 4 IntegraGen SA, Genopole Campus, Evry, France.
  • 5 INSERM, Sorbonne Université, Paris, France.
  • 6 Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France.
  • 7 Fondation Jean Dausset-CEPH (Centre d'Etude du Polymorphisme Humain), Paris, France.
  • 8 Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • 9 Service d'Exploration de la Vision et Neuro-ophtalmologie, CHRU de Lille, Lille, France.
  • 10 Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
  • 11 Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
  • 12 Clinique Jules Verne, Centre de Compétence Maladies Rares, Nantes, France.
  • 13 Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium.
  • 14 Centre for Human Genetics, University Hospitals Leuven, Belgium.
  • 15 Department of Ophthalmology, Queen Fabiola Children's University Hospital, Brussels, Belgium.
  • 16 Departments of Ophthalmology, Human Genetics, and Pediatric Surgery, Montreal Children's Hospital, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
  • 17 Service de Génétique, CHU Clermont-Ferrand, France.
  • 18 Department of Neuroscience, Psychology and Behaviour, Ulverscroft Eye Unit, University of Leicester, Leicester, United Kingdom.
  • 19 Mitovasc, UMR CNRS 6015-INSERM 1083, Université d'Angers, France.
  • 20 Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • 21 Department of Ophthalmology, Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland.
  • 22 Department of Ophthalmology, St. James's University Hospital, Leeds, United Kingdom.
  • 23 Department of Clinical Genetics, Leeds, United Kingdom.
  • 24 Service de Génétique Médicale, Hôpital de Hautepierre, Strasbourg, France.
  • 25 Laboratoire de Génétique Médicale, INSERM U1112, Strasbourg, France.
  • 26 Centre de référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), Hôpital Civil, Strasbourg, France.
  • 27 Hôpital Privé Saint Martin, Ramsay Générale de Santé, Caen, France.
  • 28 Medical Practice Stadttheater, Freiburg, Germany.
  • 29 Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
  • 30 Institute for Neurosciences of Montpellier, Montpellier University and INSERM U1051, Montpellier, France.
  • 31 Werner Reichardt Center for Integrative Neuroscience, University of Tübingen, Tübingen, Germany.
  • 32 Department of Ophthalmology, University of Essen, Essen, Germany.
  • 33 Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
  • 34 Institute of Ophthalmology, University College of London, London, United Kingdom.

摘要


Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.

KEYWORDS: CACNA1F, IRD, gene defect, icCSNB, intronic variants, minigene approach, synonymous variants