Identification of the genetic defect in the original Wagnersyndrome family

[摘要] Purpose: The aim of the present study was to determine the geneticdefect in Wagner syndrome, a rare disorder belonging to the group ofhereditary vitreoretinal degenerations. This disease has beengenetically mapped to chromosome 5q14.3.Methods: Molecular analysis was performed in the progeny of theoriginal pedigree described by Wagner in 1938. We searched forpathogenic mutations and their effects in two candidate genes, CSPG2and EDIL3, which locate to the critical chromosomal interval.Reverse transcriptase polymerase chain reaction (RT-PCR) analysis wasused to investigate potential splice defects of CSPG2 transcripts.Results: While no alterations were detected in the exons ofEDIL3, several changes were identified in the CSPG2 gene. Onlyone of the novel changes, a heterozygous G to A substitution of thefirst nucleotide in intron 8, cosegregates with the disease phenotype.This change disrupts the highly conserved splice donor sequence. Inblood cells of an index patient, we found CSPG2 transcripts withnormally spliced exon 8/9 junction but also two additional CSPG2transcripts, which were not detected in the control. One lacks theentire exon 8, while the other is missing only the last 21 bp of exon8.Conclusions: CSPG2 encodes versican, a large proteoglycan, whichis an extracellular matrix component of the human vitreous andparticipates in the formation of the vitreous gel. The splice sitemutation described here may lead to a complete lack of exon 8 in CSPG2transcripts, which shortens the predicted protein by 1754 amino acidsand leads to severe reduction of glycosaminoglycan attachment sites.

[学科分类] 生物化学/生物物理