Null retinoschisin-protein expression from an RS1 c354del1-ins18 mutation causing progressive and severe XLRS in a cross-sectional family study.
OBJECTIVE
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.
Vijayasarathy
Camasamudram
C
Section for Translational Research in Retinal and Macular Degeneration, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
Ziccardi
Lucia
L
Zeng
Yong
Y
Smaoui
Nizar
N
Caruso
Rafael C
RC
Sieving
Paul A
PA
D000328:Adult; D000818:Animals; D001284:Atrophy; D019556:COS Cells / Q000378:metabolism; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D003430:Cross-Sectional Studies; D004591:Electrophoresis, Polyacrylamide Gel; D004596:Electroretinography; D005091:Exons / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D016368:Frameshift Mutation; D006801:Humans; D054643:INDEL Mutation; D007223:Infant; D008266:Macula Lutea / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D012160:Retina / Q000503:physiopathology*; D041441:Retinoschisis / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D041623:Tomography, Optical Coherence; D014162:Transfection; D014792:Visual Acuity / Q000502:physiology
D005136:Eye Proteins; D012333:RNA, Messenger; C108726:RS1 protein, human