Purchase this article with an account.
B. Kloeckener–Gruissem, D. Bartholdi, M.–T. Abdou, D.R. Zimmermann, W. Berger; Identification of the Genetic Defect in the Original Wagner Syndrome Family . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4634.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The aim of this study was to determine the genetic defect in Wagner syndrome, a rare autosomal dominant disorder belonging to the group of hereditary vitreoretinal degenerations. This disease had been genetically mapped to chromosome 5q14.3.
The progeny of the original pedigree described by Wagner in 1938 was subjected to DNA sequencing analysis of EDIL3 and CSPG2 exons and their immediate flanking intron sequences. CSPG2 transcripts were analyzed by RT–PCR.
While no alterations were detected in EDIL3 several changes were identified in the CSPG2gene. Only one of these, a heterozygous G to A substitution of the first nucleotide in intron 8, co–segregates with the disease phenotype. This change disrupts the highly conserved GT splice donor sequence. In blood cells of an index patient we found CSPG2 transcripts with normally spliced exon 8/9 junction but also two erroneous CSPG2 transcripts. One of them lacks the entire exon 8 while the other is missing only the last 21 bps of exon 8.
CSPG2 encodes versican, a large extracellular matrix proteoglycan, which is expressed by four tissues specific variants distinguishable by the presence or absence of exons 7 and/or 8. We hypothesize that the splice defect results in ectopic expression of the V2 variant in the vitreous, thereby affecting interactions with other extracellular matrix components and consequently disturbing the ultrastructural organisation of the vitreous gel, ultimately leading to a liquefaction of the vitreous and rendering the physiological properties to the observed pathology of vitreoretinopathy. Tests to verify our hypothesis and investigate the role of the two aberrant CSPG2 transcripts are in progress.
This PDF is available to Subscribers Only