March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Molecular Modeling of RS1 Structure Indicates Two Classes of Missense Variants With Mild and Severe XLRS Phenotypes
Author Affiliations & Notes
  • Yuri V. Sergeev
    OGVFB,
    National Eye Institute, Bethesda, Maryland
  • Paul A. Sieving
    National Eye Institute, Bethesda, Maryland
  • Ajoy Vincent
    Electrophysiology, Moorfields Eye Hospital, London, United Kingdom
  • Anthony G. Robson
    Electrophysiology, Moorfields Eye Hospital, London, United Kingdom
    Institute of Ophthalmology, University College, London, United Kingdom
  • Anthony T. Moore
    Institute of Ophthalmology, University College, London, United Kingdom
  • Andrew R. Webster
    Institute of Ophthalmology, University College, London, United Kingdom
  • Graham E. Holder
    Electrophysiology, Moorfields Eye Hospital, London, United Kingdom
    Institute of Ophthalmology, University College, London, United Kingdom
  • Footnotes
    Commercial Relationships  Yuri V. Sergeev, None; Paul A. Sieving, None; Ajoy Vincent, None; Anthony G. Robson, None; Anthony T. Moore, None; Andrew R. Webster, None; Graham E. Holder, None
  • Footnotes
    Support  Z01-EY000476-01
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 5686. doi:
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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)

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Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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.

Conclusions: : 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.

Keywords: computational modeling • mutations • electroretinography: clinical 
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