IOVS British Journal of Pharmacology
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(Investigative Ophthalmology and Visual Science. 2005;46:2726-2735.)
© 2005 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-0057
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Identification of a Novel Splice Site Mutation of the CSPG2 Gene in a Japanese Family with Wagner Syndrome

Tatsuro Miyamoto,1,2 Hiroshi Inoue,1 Yukiko Sakamoto,1 Eiji Kudo,1 Takeshi Naito,2 Takako Mikawa,3 Yoichi Mikawa,3 Yasushi Isashiki,4 Dai Osabe,5 Shuichi Shinohara,5 Hiroshi Shiota,2 and Mitsuo Itakura1

1From the Division of Genetic Information, Institute for Genome Research, and the 2Department of Ophthalmology and Visual Neuroscience, Institute of Health Biosciences, The University of Tokushima, Tokushima, Japan; the 3Mikawa Eye Clinic, Tokushima, Japan; the 4Department of Ophthalmology, Kagoshima University Faculty of Medicine, Kagoshima, Japan; and the 5Department of Bioinformatics, Division of Life Science Systems, Fujitsu, Ltd., Tokyo, Japan.

PURPOSE. To investigate the genetic basis and clinical variability of Wagner syndrome, a rare, dominantly inherited vitreoretinopathy.

METHODS. Clinical examination, linkage analysis, and mutational screening were performed in a large, three-generation, consanguineous Japanese family with Wagner syndrome. The effect of splice site mutation was assessed by reverse transcriptase–polymerase chain reaction (RT-PCR) analysis with lymphoblastoid cell total RNAs generated from affected individuals.

RESULTS. Ocular phenotypes of affected members included an empty vitreous with fibrillary condensations, avascular membrane, perivascular sheathing, and progressive chorioretinal dystrophy and were similar to those of the original Wagner syndrome family. All affected eyes examined exhibited pseudoexotropia with ectopic fovea. No systemic manifestations were observed. Genetic linkage confirmed disease segregation with the previously identified WGN1 locus on 5q13-q14. A heterozygous A->G transversion at the second base of the 3'-acceptor splice site of intron 7 (c.4004-2 A->G) of the chondroitin sulfate proteoglycan 2 (CSPG2) gene that cosegregated with the disease was identified. Results of RT-PCR analysis indicated that the c.4004-2 A->G mutation activates a cryptic splice site, located 39 bp downstream from the authentic 3' splice acceptor site.

CONCLUSIONS. This linkage study confirmed the genetic homogeneity of the Wagner syndrome. CSPG2 encodes versican, a large chondroitin sulfate proteoglycan, which, in vitreous, binds to hyaluronan and link protein and forms large aggregates that are important for maintaining structural integrity. Although the CSPG2 gene has been excluded as a candidate for causing Wagner syndrome, these data emphasize the necessity of further mutational screening in new families and careful functional characterization.




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