June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Molecular modeling of functional domain of ABCA4: towards understanding the genotype-to-phenotype relationships in Stargardt’s disease
Author Affiliations & Notes
  • Yuri Sergeev
    OGVFB, National Eye Institute, Bethesda, MD
  • Katherine Pogrebniak
    OGVFB, National Eye Institute, Bethesda, MD
    Princeton University, Princeton, NJ
  • Benedetto Falsini
    OGVFB, National Eye Institute, Bethesda, MD
    Ophthalmology, Catholic University, Rome, Italy
  • Wadih Zein
    OGVFB, National Eye Institute, Bethesda, MD
  • Kerry Goetz
    EyeGene, OGVFB, National Eye Institute, Bethesda, MD
  • Jillian Huang
    Kellogg Eye Center, University of Michigan, Ann Arbor, MI
  • Crandall Peeler
    Kellogg Eye Center, University of Michigan, Ann Arbor, MI
  • Kanishka Jayasundera
    Kellogg Eye Center, University of Michigan, Ann Arbor, MI
  • Brian Brooks
    OGVFB, National Eye Institute, Bethesda, MD
  • Paul Sieving
    OGVFB, National Eye Institute, Bethesda, MD
  • Footnotes
    Commercial Relationships Yuri Sergeev, None; Katherine Pogrebniak, None; Benedetto Falsini, None; Wadih Zein, None; Kerry Goetz, National Eye Institute/NIH (E); Jillian Huang, None; Crandall Peeler, None; Kanishka Jayasundera, None; Brian Brooks, None; Paul Sieving, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1325. doi:
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      Yuri Sergeev, Katherine Pogrebniak, Benedetto Falsini, Wadih Zein, Kerry Goetz, Jillian Huang, Crandall Peeler, Kanishka Jayasundera, Brian Brooks, Paul Sieving; Molecular modeling of functional domain of ABCA4: towards understanding the genotype-to-phenotype relationships in Stargardt’s disease. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1325.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: ABCA4 is an ATP binding cassette protein transporter. Mutations affecting the ABCA4 transporter protein are known to cause Stargardt’s macular degeneration, but very little is known about the structure of ABCA4, making it difficult to understand how these mutations affect the function of ABCA4 as a protein transporter. Here we performed molecular modeling of the functional domain which includes trans-membrane and nucleotide-binding domains, a part of ABCA4 polypeptide responsible for the flipping of N-retinylidene PE over the disc membrane.

Methods: The functional domain was modeled by homology, refined and equilibrated using molecular dynamics. This model was used to predict structural perturbations caused by mutations found in affected human subjects. Overall genotype scoring function was derived from free energy changes for the ABCA4 open/close conformers was calculated for each mutation (Sergeev et al, Hum Mol Genetics, 2010). We then evaluated possible correlations of this modeling with phenotypes of patients from the NEI, EyeGENE database, Italian and Kellogg Eye Center Stargardt’s patients (42 genotypes total).

Results: In the selected group of 15 patients we found an association between the overall genotype score and the age of disease onset known to be related to the severity of retinal disease (Pearson’s r = - 0.71, Adj. R-square = 0.46). Similar association between these parameters was observed for 7 NEI patients enrolled in EyeGENE (Pearson’s r = - 0.76, Adj. R-square = 0.53). Finally, these data were combined with data from Italian Stargardt’s patients. The total dataset of 28 patients showed a linear association between predicted severities and the age of disease onset (Pearson’s r = - 0.67, Adj. R-square = 0.42). Similar result was obtained for 12 patients from the Kellogg Eye Center (Pearson’s r = - 0.76, Adj. R-square=0.54).

Conclusions: The overall impact score for each individual analyzed was associated with the age of retinal disease onset. The functional activity suggested by the model is in agreement with recent experimental data on ABCA4 as a ‘flippase’ protein. Thus, molecular modeling of the ABCA4 functional domains and the scoring system derived in our work has a potential to be used for a study of genotype-to-phenotype relationships in Stargardt’s disease.

Keywords: 539 genetics • 696 retinal degenerations: hereditary • 473 computational modeling  
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