April 2010
Volume 51, Issue 13
ARVO Annual Meeting Abstract  |   April 2010
X-Linked Juvenile Retinoschisis Resulting From a Novel Mutation in the RS1 Gene: Potential Germline Mosaicism
Author Affiliations & Notes
  • X. Wang
    OGVFB, National Eye Institute, Bethesda, Maryland
  • Y. V. Sergeev
    OGVFB, National Eye Institute, Bethesda, Maryland
  • C. Antolik
    OGVFB, National Eye Institute, Bethesda, Maryland
  • Footnotes
    Commercial Relationships  X. Wang, None; Y.V. Sergeev, None; C. Antolik, None.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 3084. doi:
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      X. Wang, Y. V. Sergeev, C. Antolik; X-Linked Juvenile Retinoschisis Resulting From a Novel Mutation in the RS1 Gene: Potential Germline Mosaicism. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3084.

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

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Purpose: : X-linked juvenile retinoschisis (XLRS) is the most common inherited retinal dystrophy in males. Early-onset loss of central vision results from the formation of foveo-macular cavities in the inner retina. XLRS is highly penetrant and is caused by mutations in the RS1 gene, which encodes the secreted protein retinoschisin, which exists in a homo-octamer in the extracellular matrix. There are >170 unique DNA variants in the RS1 gene, consisting of missense, nonsense, insertion/deletion, and splice site mutations. Here, we report a novel mutation in the RS1 gene and describe its transmission and structural consequences.

Methods: : Peripheral blood DNA was extracted from patients enrolled in eyeGENE®, the National Ophthalmic Disease Genotyping and Phenotyping Network. The six exons that encode retinoschisin were amplified by PCR, using primers located in the introns. Exons were subjected to direct sequencing. Coding sequences and ~25bp of flanking intronic sequences were examined. Confirmation of inheritance was performed by fragment length analysis using commercially available linkage mapping sets. In silico modeling was performed to understand the structural effects of this novel missense variant.

Results: : The proband, a 14 year-old male, was found to have a novel c.626G>C mutation, causing a change from arginine to proline at amino acid 209 (R209P). This amino acid is conserved in dog, cattle, mouse and zebra fish homologs of RS1. Independent mutations at nucleotide 625 (C>T and C>G), and a different mutation at nucleotide 626 (G>A), result in substitution of either a cysteine, glycine or histidine residue, respectively, for arginine 209. The proband’s mother was unaffected and did not have the familial mutation, suggestive of germline mosaicism. Linkage analysis of X chromosome STR markers confirmed a consistent inheritance between proband and his mother.

Conclusions: : The diagnosis of XLRS in the proband was confirmed by the identification of a novel mutation (c.626G>C; p.R209P) in the RS1 gene. In silico modeling suggests that the introduction of proline at residue 209 might affect normal protein function.

Keywords: genetics • clinical laboratory testing • mutations 

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