Null Retinoschisin-Protein Expression from an RS1 c354del1-ins18 Mutation Causing Progressive and Severe XLRS in a Cross-Sectional Family Study

作者：Vijayasarathy Camasamudram; Ziccardi Lucia; Zeng Yong; Smaoui Nizar; Caruso Rafael C; Sieving Paul A^*

来源：Investigative Ophthalmology & Visual Science, 2009, 50(11): 5375-5383.

DOI：10.1167/iovs.09-3839

PURPOSE. To explore the retinoschisin (RS1) protein biochemical phenotype from an RS1 exon-5 deletion/insertion frame-shift mutation in a family with X-linked retinoschisis (XLRS) and describe the clinical and electrophysiological features.
METHODS. Six XLRS males underwent ophthalmic examination and electroretinogram (ERG) recording. The RS1 gene was sequenced. Mutant RS1-RNA and protein expression were assessed by transfecting COS-7 cells with minigene constructs.
RESULTS. All six males carried the RS1 c354del1-ins18 mutation in which an 18-bp insertion replaced nucleotide 354, duplicating the adjacent upstream intron 4-to-exon 5 junction and creating a premature termination codon downstream. Analysis indicated normal pre-mRNA splicing producing mRNA transcripts. Truncated RS1 protein was expressed transiently but was degraded rapidly by a proteasomal pathway rather than by nonsense-mediated mRNA decay. Two boys, 1.5 and 5 years of age, had foveal cysts and minimal peripheral schisis, and retained near-normal scotopic b-wave amplitude and normal ERG waveforms. The 5-year-old's ERG was diminished when repeated 3 years later. Four older XLRS relatives 32 to 45 years old had substantial b-wave loss and strongly electronegative ERGs; three had overt macular atrophy. Cross-sectional family analysis showed the b-/a-wave amplitude ratio as inversely related to age in the six males.
CONCLUSIONS. The c354del1-ins18 mutation caused an RS1-null biochemical phenotype and a progressive clinical phenotype in a 5-year-old boy, whereas the older XLRS relatives had macular atrophy and marked ERG changes. The phenotypic heterogeneity with age by cross-sectional study of this family mutation argues that XLRS disease is not stationary and raises questions regarding factors involved in progression. (Invest Ophthalmol Vis Sci. 2009;50:5375-5383) DOI:10.1167/iovs.093839

• 出版日期2009-11