Molecular Modeling of Retinoschisin and Functional Analysis of Pathogenic Mutations From X-Linked Retinoschisis

Abstract

Purpose: : RS1

Methods: : Here we report molecular modeling of the RS protein and consider perturbations caused by mutations found in human XLRS affected subjects. The RS protein structure was modeled by homology to the discoidin domain. We then evaluated possible correlations of this modeling with retinal function studied in 60 XLRS patients having one of 27 missense mutations using electroretinogram (ERG) a- and b- waves. The dark adapted (b/a-wave) ratio reflects retinal visual signal transfer through the synapse between the photoreceptors (a-wave) and the bipolar cells (b-wave) of the rod circuit. We sorted the ERG b/a-ratios by the mutation impact on modeled by homology protein atomic structure using a score combining protein stabilization energy and a Grantham distance.

Results: : The majority of RS mutations which cause a minimal structure perturbation were target to the protein surface. For these mutations patients’ b/a-ratios were quite similar across younger and older subjects. Maximum structural perturbations resulted from the removal or insertion of cysteine residues or were due to changes in the hydrophobic core. These were associated with a considerable age difference in the b/a-ratio and caused a significantly smaller ratio at younger ages for XLRS.

Conclusions: : The molecular modeling suggests an association of the predicted alteration and/or damage to the retinoschisin protein structure due to mutations with XLRS disease severity. Homologous ERG changes with age were observed in natural history studies of mice carrying a recombinant knockout RS1 gene. This modeling indicates that mutational change in RS protein structure affect the phenotype of XLRS.

Keywords: proteins encoded by disease genes • computational modeling • electroretinography: clinical