June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Whole exome sequencing identifies mutations in LRIT3 as a cause for autosomal recessive complete congenital stationary night blindness
Author Affiliations & Notes
  • Christina Zeitz
    Institut de la Vision, Univ Pierre et Marie Curie Paris 6, INSERM, UMR_S968; CNRS, UMR_7210, Paris, F-75012, France
  • Samuel Jacobson
    University of Pennsylvania, Scheie Eye Institute, Philadelphia 19104, PA
  • Christian Hamel
    Inserm U. 583, Physiopathologie et thérapie des déficits sensoriels et moteurs, Institut des Neurosciences de Montpellier, Hôpital Saint-Eloi, Montpellier, 34295 Cedex 05, France
  • Kinga Bujakowska
    Institut de la Vision, Univ Pierre et Marie Curie Paris 6, INSERM, UMR_S968; CNRS, UMR_7210, Paris, F-75012, France
  • Marion Neuillé
    Institut de la Vision, Univ Pierre et Marie Curie Paris 6, INSERM, UMR_S968; CNRS, UMR_7210, Paris, F-75012, France
  • Elise Orhan
    Institut de la Vision, Univ Pierre et Marie Curie Paris 6, INSERM, UMR_S968; CNRS, UMR_7210, Paris, F-75012, France
  • Xavier Zanlonghi
    Service Exploration Fonctionnelle de la Vision et Centre basse vision de la Clinique Sourdille, Nantes 44000, France
  • Jose Sahel
    Univ Pierre et Marie Curie Paris 6, INSERM, UMR_S968; CNRS, UMR_7210; CHNO, INSERM-DHOS CIC 503; Fondation Ophtalmologique Adolphe de Rothschild, Paris; Académie des Sciences-Institut de France, Paris, F-75012, France
  • Shomi Bhattacharya
    UCL-Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, United Kingdom
    Department of Cellular Therapy and Regenerative Medicine, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Isla Cartuja, Seville 41902, Spain
  • Isabelle Audo
    UCL-Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, United Kingdom
    Univ Pierre et Marie Curie Paris 6, INSERM, UMR_S968; CNRS, UMR_7210; CHNO, INSERM-DHOS CIC 503, Paris, F-75012, France
  • Footnotes
    Commercial Relationships Christina Zeitz, None; Samuel Jacobson, None; Christian Hamel, None; Kinga Bujakowska, None; Marion Neuillé, None; Elise Orhan, None; Xavier Zanlonghi, None; Jose Sahel, UPMC/Essilor (P), Second Sight (F); Shomi Bhattacharya, None; Isabelle Audo, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 3350. doi:
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      Christina Zeitz, Samuel Jacobson, Christian Hamel, Kinga Bujakowska, Marion Neuillé, Elise Orhan, Xavier Zanlonghi, Jose Sahel, Shomi Bhattacharya, Isabelle Audo, CSNB study group; Whole exome sequencing identifies mutations in LRIT3 as a cause for autosomal recessive complete congenital stationary night blindness. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3350.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Mutations in NYX, GRM6, TRPM1 and GPR179 expressed in ON-bipolar cells, lead to a disruption of the ON-bipolar response and reduced night vision. This dysfunction is present in patients with complete congenital stationary night blindness (cCSNB). Although many cases of cCSNB have been caused by mutations in these genes, in some of the patients the gene defect remains unknown. Here we sought to identify the disease-causing gene in the remaining patients by whole exome sequencing.

Methods: Whole exome sequencing was applied to one simplex cCSNB case lacking mutations in the known genes. Tissue specific and prediction databases were used to define the most promising candidate gene defect. In addition, Sanger sequencing in other CSNB patients was performed. RT and immunolocalization with confocal microscopy studies of the candidate gene were applied.

Results: Whole exome sequencing led to the identification of a missense mutation (c.983G>A p.Cys328Tyr) and nonsense mutation (c.1318C>T p.Arg440*) in a gene LRIT3 coding for a Leucine-Rich Repeat (LRR), immunoglobulin-like and transmembrane domains 3 protein. Subsequent Sanger sequencing of 89 individuals with CSNB identified another cCSNB case harboring a nonsense mutation (c.1151C>G p.Ser384*) and a deletion (c.1538_1539del p.Ser513Cysfs*59) in the same gene. Human LRIT3 antibody staining revealed a punctate-labeling pattern in the outer plexiform layer of the human retina, resembling dendritic tips of bipolar cells as found in other proteins implicated in cCSNB.

Conclusions: Including the current study, mutations in five genes have been implicated in cCSNB. All localize postsynaptically to the photoreceptors in the retina in ON-bipolar cells. The mutation spectrum described here affect different domains of LRIT3, including the Cys328, which is predicted to form a disulfide bond in the Ig-like domain. The three other mutations represent two nonsense mutations and a frameshift mutation, which are located in the last exon. Thus it is most likely that mutant mRNA products escape nonsense-mediated decay. Further functional studies will eventually clarify the exact role and pathogenic mechanism of LRIT3 within the ON-bipolar cell pathway.

Keywords: 534 gene mapping • 435 bipolar cells • 563 inner retina dysfunction: hereditary  
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