Dataset of eye disease-related proteins analyzed using the unfolding mutation screen

McCafferty, Caitlyn L.; Sergeev, Yuri V.

doi:10.1038/sdata.2016.112

Cited by 13 publications

(15 citation statements)

References 28 publications

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“…Homology modelling has previously been used to produce a predicted 3D structure of TIMP3 and using UCSF Chimera 1.11.2, a graphic has been prepared for this review with SFD-associated variants highlighted ( Fig. 3) (McCafferty and Sergeev, 2016;Pettersen et al, 2004). However, it is clear that although most SFD-associated TIMP3 variants are in the C-terminal domain, SFD can also be caused by the N-terminal domain variants Cys24Arg and Ser38Cys and severity is not easily correlated with the amino acid residue effected ( Fig.…”

Section: Association Of Phenotype With Different Timp3 Variantsmentioning

confidence: 99%

“…AL is a NIHR Senior Investigator. The 3D schematic is derived from a pdb file produced by previously published homology modelling (McCafferty & Sergeev, 2016). Cysteine residues are represented by blue circles on the linear diagram (A) and with arrows on the 3D schematic (B) and disulphide bonds between cysteine residues are represented by black lines.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…A representation of a theoretical model of the structure of TIMP3 based on previously published homology modelling(McCafferty & Sergeev, 2016). The chain is shown as a ribbon and coloured based on the proximity to the N-terminus (blue) or the C-terminus (red), such that the N-terminal domain is blue and green and the C-terminal domain is yellow, orange, and red.…”

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confidence: 99%

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Sorsby fundus dystrophy – A review of pathology and disease mechanisms

Christensen

Brown

Cree

et al. 2017

Experimental Eye Research

143

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Sorsby fundus dystrophy (SFD) is an autosomal dominant macular dystrophy with an estimated prevalence of 1 in 220,000 and an onset of disease around the 4th to 6th decade of life. Similar to age-related macular degeneration (AMD), ophthalmoscopy reveals accumulation of protein/lipid deposits under the retinal pigment epithelium (RPE), referred to as drusen, in the eyes of patients with SFD. SFD is caused by variants in the gene for tissue inhibitor of metalloproteinases-3 (TIMP3), which has been found in drusen-like deposits of SFD patients. TIMP3 is constitutively expressed by RPE cells and, in healthy eyes, resides in Bruch's membrane. Most SFD-associated TIMP3 variants involve the gain or loss of a cysteine residue. This suggests the protein aberrantly forms intermolecular disulphide bonds, resulting in the formation of TIMP3 dimers. It has been demonstrated that SFD-associated TIMP3 variants are more resistant to turnover, which is thought to be a result of dimerisation and thought to explain the accumulation of TIMP3 in drusen-like deposits at the level of Bruch's membrane. An important function of TIMP3 within the outer retina is to regulate the thickness of Bruch's membrane. TIMP3 performs this function by inhibiting the activity of matrix metalloproteinases (MMPs), which have the function of catalysing breakdown of the extracellular matrix. TIMP3 has an additional function to inhibit vascular endothelial growth factor (VEGF) signalling and thereby to inhibit angiogenesis. However, it is unclear whether SFD-associated TIMP3 variant proteins retain these functions. In this review, we discuss the current understanding of the potential mechanisms underlying development of SFD and summarise all known SFD-associated TIMP3 variants. Cell culture models provide an invaluable way to study disease and identify potential treatments. These allow a greater understanding of RPE physiology and pathophysiology, including the ability to study the blood-retinal barrier as well as other RPE functions such as phagocytosis of photoreceptor outer segments. This review describes some examples of such recent in vitro studies and how they might provide new insights into degenerative diseases like SFD. Thus far, most studies on SFD have been performed using ARPE-19 cells or other, less suitable, cell-types. Now, induced pluripotent stem cell (iPSC) technologies allow the possibility to non-invasively collect somatic cells, such as dermal fibroblast cells and reprogram those to produce iPSCs. Subsequent differentiation of iPSCs can generate patient-derived RPE cells that carry the same disease-associated variant as RPE cells in the eyes of the patient. Use of these patient-derived RPE cells in novel cell culture systems should increase our understanding of how SFD and similar macular dystrophies develop.

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Section: Association Of Phenotype With Different Timp3 Variantsmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

mentioning

confidence: 99%

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Sorsby fundus dystrophy – A review of pathology and disease mechanisms

Christensen

Brown

Cree

et al. 2017

Experimental Eye Research

143

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“…The corresponding UMS heat maps and foldability structures are available for RHO, CFH, and RPE65 along with 12 other proteins from McCafferty & Sergeev (ref. 31). …”

Section: Resultsmentioning

confidence: 99%

“…The extended UMS library and data descriptors for 15 proteins from inherited eye disease is available from McCafferty & Sergeev (ref. 31). …”

Section: Methodsmentioning

confidence: 99%

In silico Mapping of Protein Unfolding Mutations for Inherited Disease

McCafferty

Sergeev

2016

Sci Rep

Self Cite

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The effect of disease-causing missense mutations on protein folding is difficult to evaluate. To understand this relationship, we developed the unfolding mutation screen (UMS) for in silico evaluation of the severity of genetic perturbations at the atomic level of protein structure. The program takes into account the protein-unfolding curve and generates propensities using calculated free energy changes for every possible missense mutation at once. These results are presented in a series of unfolding heat maps and a colored protein 3D structure to show the residues critical to the protein folding and are available for quick reference. UMS was tested with 16 crystal structures to evaluate the unfolding for 1391 mutations from the ProTherm database. Our results showed that the computational accuracy of the unfolding calculations was similar to the accuracy of previously published free energy changes but provided a better scale. Our residue identity control helps to improve protein homology models. The unfolding predictions for proteins involved in age-related macular degeneration, retinitis pigmentosa, and Leber’s congenital amaurosis matched well with data from previous studies. These results suggest that UMS could be a useful tool in the analysis of genotype-to-phenotype associations and next-generation sequencing data for inherited diseases.

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Inherited Eye Disease-Related Proteins: Molecular Modeling and Global Computational Mutagenesis

Sergeev

2024

Essentials in Ophthalmology

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Dataset of eye disease-related proteins analyzed using the unfolding mutation screen

Cited by 13 publications

References 28 publications

Sorsby fundus dystrophy – A review of pathology and disease mechanisms

Sorsby fundus dystrophy – A review of pathology and disease mechanisms

In silico Mapping of Protein Unfolding Mutations for Inherited Disease

Inherited Eye Disease-Related Proteins: Molecular Modeling and Global Computational Mutagenesis

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