X-linked retinoschisis: RS1 mutation severity and age affect the ERG phenotype in a cohort of 68 affected male subjects.

A monogenic condition, X-linked retinoschisis (XLRS) is a leading genetic cause of macular degeneration in young males and affects 1:5000 to 1:25,000.1 It is caused by mutations in the retinoschisin gene (RS1) at Xp22.2 Nearly 150 disease-causing RS1 mutations have been identified.3 RS1 encodes a 24-kDa protein, retinoschisin (RS), which contains a discoidin domain and is found in the retina and pineal gland.4 Retinoschisin is thought to be important for cell adhesion and cell signaling because the protein has been demonstrated in the photoreceptor synapse onto bipolar cells.5 RS is associated with the Na+/K+ ATPase in the photoreceptor inner segment membrane.6 Atomic force microscopy implicates a structural role for retinoschisin in organizing lipid membranes, which may help to stabilize retinal cell integrity.7 XLRS subjects exhibit considerable heterogeneity on clinical examination and functional vision testing.8 Although most XLRS-affected males first come to attention for reduced acuity during school screening, some XLRS experience retinal detachments in infancy. In addition, our clinical cohort suggests that XLRS subjects rarely retain sufficient visual function to obtain an unrestricted driver's license by the fourth and fifth decades of life. The consequence of abnormal retinoschisin protein or complete absence of RS on retinal function can be evaluated clinically using the full-field electroretinogram (ERG). The characteristic dark-adapted bright-flash ERG response in XLRS is an “electronegative waveform” in which the b-wave amplitude is disproportionately smaller than the normal or near-normal a-wave. ERG a-wave modeling has shown that phototransduction remains normal in some XLRS subjects despite reduced b-waves,9 indicating that one site of dysfunction lies beyond the photoreceptors. Abnormal timing of the light-adapted 30-Hz cone flicker ERG response is also reported, further suggesting dysfunction of the inner retina when associated with normal a-wave responses.10 In this genotype-phenotype study, we used the full-field ERG to evaluate retinal function of 68 XLRS subjects who were examined and genotyped at the National Eye Institute (NEI). The RS1 gene contains six exons that encode for a signal sequence (exons 1 and 2), a retinoschisin domain (exon 3), and the discoidin domain (exons 4–6).2 Most RS1 mutations analyzed to date have implicated primarily a loss function rather than an abnormal function from the mutant protein.7 Signal sequence domain mutations impair protein transport to the endoplasmic reticulum and consequently yield a functional null-protein effect. Some discoidin domain mutations allow the production of retinoschisin mutant protein, but it is rapidly degraded and lost.11 The diversity and complexity of RS1 mutations precluded our incorporating all molecular nuances in a phenotype analysis. Instead, we simplified the approach by segregating the RS1 mutations into two groups based on the putative severity of effect on protein function. We included molecular modeling12 and, in some cases, biochemical analysis11 in this approach to classify our subjects as having either a less or a more severe mutation and a putative effect on the resultant protein. We then examined for an association of disease phenotype (ERG measurements) with genotype severity.