Applied Genetic Technologies Corporation (AGTC)

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X-linked juvenile retinoschisis: Clinical diagnosis, genetic analysis, and molecular mechanisms

Robert S. Molday a,*, Ulrich Kellner b
, Bernhard H.F. Weber c
aDepartment of Biochemistry and Molecular Biology, Centre of Macular Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, B.C. V6T 1Z3, Canada b Center of Rare Retinal Disease, AugenZentrum Siegburg, MVZ ADTC Siegburg GmbH, Europaplatz 3, D-53721 Siegburg, Germany
cUniversity of Regensburg, Institute of Human Genetics, Franz-Josef-Strauss-Allee 11, D-97053 Regensburg, Germany

X-linked juvenile retinoschisis (XLRS, MIM 312700) is a common early onset macular degeneration in
males characterized by mild to severe loss in visual acuity, splitting of retinal layers, and a reduction in
the b-wave of the electroretinogram (ERG). The RS1 gene (MIM 300839) associated with the disease
encodes retinoschisin, a 224 amino acid protein containing a discoidin domain as the major structural
unit, an N-terminal cleavable signal sequence, and regions responsible for subunit oligomerization.
Retinoschisin is secreted from retinal cells as a disulphide-linked homo-octameric complex which binds
to the surface of photoreceptors and bipolar cells to help maintain the integrity of the retina. Over 190
disease-causing mutations in the RS1 gene are known with most mutations occurring as
non-synonymous changes in the discoidin domain. Cell expression studies have shown that diseaseassociated missense mutations in the discoidin domain cause severe protein misfolding and retention
in the endoplasmic reticulum, mutations in the signal sequence result in aberrant protein synthesis, and
mutations in regions flanking the discoidin domain cause defective disulphide-linked subunit assembly,
all of which produce a non-functional protein. Knockout mice deficient in retinoschisin have been
generated and shown to display most of the characteristic features found in XLRS patients. Recombinant
adeno-associated virus (rAAV) mediated delivery of the normal RS1 gene to the retina of young knockout
mice result in long-term retinoschisin expression and rescue of retinal structure and function providing
a ‘proof of concept’ that gene therapy may be an effective treatment for XLRS.
2012 Elsevier Ltd. All rights reserved

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