May 2004
Volume 45, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2004
Monogenic inheritance of Leber congenital amaurosis: causation by a novel mutation in CRB1.
H. Abouzeid; Y. Li; S. Dharmaraj; O. Sundin; I. Maumenee
Author Affiliations & Notes
  • H. Abouzeid
    The Johns Hopkins Center for Hereditary Eye Diseases,
    Johns Hopkins University, Baltimore, MD
    Jules Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland
  • Y. Li
    The Johns Hopkins Center for Hereditary Eye Diseases,
    Johns Hopkins University, Baltimore, MD
  • S. Dharmaraj
    The Johns Hopkins Center for Hereditary Eye Diseases,
    Laboratory of Developmental Genetics,
    Johns Hopkins University, Baltimore, MD
  • O. Sundin
    Laboratory of Developmental Genetics,
    Johns Hopkins University, Baltimore, MD
  • I. Maumenee
    The Johns Hopkins Center for Hereditary Eye Diseases,
    Johns Hopkins University, Baltimore, MD
  • Footnotes
    Commercial Relationships  H. Abouzeid, None; Y. Li, None; S. Dharmaraj, None; O. Sundin, None; I. Maumenee, None.
  • Footnotes
    Support  Fight for Sight
Investigative Ophthalmology & Visual Science May 2004, Vol.45, 4730. doi:
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      H. Abouzeid, Y. Li, S. Dharmaraj, O. Sundin, I. Maumenee; Monogenic inheritance of Leber congenital amaurosis: causation by a novel mutation in CRB1. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4730.

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Abstract

Abstract: : Purpose: To study the molecular basis of Leber congenital amaurosis, a genetically and phenotypically heterogeneous disease resulting in loss of vision from birth. Six genes and three loci have been associated with LCA, which is inherited as an autosomal recessive disease, with the exception of autosomal dominant CRX mutations. Methods: We studied a consanguineous six–generation family in which four individuals were affected with LCA. Ophthalmological examination and linkage analysis of eight individuals using polymorphic markers in and near the known LCA genes and loci was performed, followed by sequencing of CRB1 gene exons. Results: Definitive linkage was established to the CRB1 gene, with a maximal two–point LOD score of 5.20. Sequencing identified a novel glycine to arginine substitution (p.G1103R) at a highly conserved site in exon 9 of the CRB1 gene, which plays an important role in the differentiation and functional architecture of photoreceptors. This mutation was not detected in 104 control chromosomes. Affected individuals had severe visual impairment, no detectable ERG, high hyperopia and their fundus exhibited advanced pigmentary abnormalities. Retinal thickness was measured by OCT in one proband, and found to be twice that of a normal retina. Conclusions: We have identified a novel LCA–related CRB1 mutation associated with a severe clinical presentation. This is the third reported case in which genetic linkage analysis securely places a CRB1 mutation as a monogenic causative factor in Leber congenital amaurosis, and the second report of an increased retinal thickness associated with a CRB1 mutation. Monogenic inheritance of the CRB1–Leber phenotype in a pedigree is especially interesting in view of the fact that most CRB1 mutations are associated with retinitis pigmentosa, which is a milder condition. This supports the hypothesis that the character of the mutation itself, rather than multigenic factors, determine whether CRB1 mutations will produce a Leber or RP phenotype

Keywords: retinal degenerations: hereditary • linkage analysis • gene/expression 
© 2004, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Permission to republish any abstract or part of an abstract in any form must be obtained in writing from the ARVO Office prior to publication.
Copyright © 2024 Association for Research in Vision and Ophthalmology.
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