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Yuri V. Sergeev, Paul A. Sieving, Ajoy Vincent, Anthony G. Robson, Anthony T. Moore, Andrew R. Webster, Graham E. Holder; Molecular Modeling of RS1 Structure Indicates Two Classes of Missense Variants With Mild and Severe XLRS Phenotypes. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5686.
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© ARVO (1962-2015); The Authors (2016-present)
To apply a model of RS1 structure to clinical electrophysiological data obtained in a cohort of patients with X-linked retinoschisis (XLRS), a vitreoretinal degeneration consequent upon mutations in the RS1 gene.
An independent cohort of 38 patients with one of 18 missense changes in RS1 were ascertained (Moorfields Eye Hospital, London, UK). All underwent full-field ERG testing incorporating the International-standards. The pathogenic mutation perturbations in RS1 protein structure evaluated using molecular modeling. The missense changes were subdivided in two classes (Class I=less severe; Class II=severe) using computed severity. Patients (≤35 y/o) were segregated into 4 groups based on mutation severity and age (younger group = 9 y/o mean; older group = 24 y/o mean). Full-field ERG parameters including the dark-adapted bright flash ERG (DA 11.0) a- and b- wave amplitudes and the b/a-wave ratio were compared with the computed severity of RS1 perturbations.
The majority of Class I mutations showed no changes involving cysteine residues; Class II mutations caused severe perturbations due to the removal or insertion of cysteine residues or due to changes in the hydrophobic core. The dark-adapted bright flash ERG was electronegative (b/a ratio < 1) in most cases but there was significant variability. Class II mutations yielded lower mean values of ERG b/a-ratios than Class I mutations in both the younger (0.76 v. 0.94) and older age groups (0.87 v. 1.18). For both Class I and Class II groups the b/a-ratios were lower in younger subjects.
Molecular modeling predicts an association between the type of structural RS1 alterations and the severity of XLRS as measured by full-field electroretinography. Age-related differences in dark-adapted ERG parameters are consistent with those reported previously in the RS1 knockout mouse.
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