Identification of the genetic defect in the original Wagner syndrome family.
OBJECTIVE
The aim of the present study was to determine the genetic defect in Wagner syndrome, a rare disorder belonging to the group of hereditary vitreoretinal degenerations. This disease has been genetically mapped to chromosome 5q14.3.


METHODS
Molecular analysis was performed in the progeny of the original pedigree described by Wagner in 1938. We searched for pathogenic mutations and their effects in two candidate genes, CSPG2 and EDIL3, which locate to the critical chromosomal interval. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis was used to investigate potential splice defects of CSPG2 transcripts.


RESULTS
While no alterations were detected in the exons of EDIL3, several changes were identified in the CSPG2 gene. Only one of the novel changes, a heterozygous G to A substitution of the first nucleotide in intron 8, cosegregates with the disease phenotype. This change disrupts the highly conserved splice donor sequence. In blood cells of an index patient, we found CSPG2 transcripts with normally spliced exon 8/9 junction but also two additional CSPG2 transcripts, which were not detected in the control. One lacks the entire exon 8, while the other is missing only the last 21 bp of exon 8.


CONCLUSIONS
CSPG2 encodes versican, a large proteoglycan, which is an extracellular matrix component of the human vitreous and participates in the formation of the vitreous gel. The splice site mutation described here may lead to a complete lack of exon 8 in CSPG2 transcripts, which shortens the predicted protein by 1754 amino acids and leads to severe reduction of glycosaminoglycan attachment sites.
Kloeckener-Gruissem
Barbara
B
Division of Medical Molecular Genetics and Gene Diagnostics, University of Zurich, Zurich, Switzerland. kloeckener@medgen.unizh.ch
Bartholdi
Deborah
D
Abdou
Marie-Therese
MT
Zimmermann
Dieter R
DR
Berger
Wolfgang
W
D000225:Adenine; D016022:Case-Control Studies; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics*; D020090:Chromosome Segregation; D004274:DNA, Recombinant; D005091:Exons; D005128:Eye Diseases / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D006147:Guanine; D006579:Heterozygote; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics*; D008297:Male; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000097:blood; D012162:Retinal Degeneration / Q000235:genetics*; D013577:Syndrome; D053675:Versicans; D014822:Vitreous Body
D011508:Chondroitin Sulfate Proteoglycans; D004274:DNA, Recombinant; D037181:Lectins, C-Type; D012333:RNA, Messenger; C508322:VCAN protein, human; D053675:Versicans; D006147:Guanine; D000225:Adenine