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Functional and clinical data of Best vitelliform macular dystrophy patients with mutations in the BEST1 gene.

Querques G, Zerbib J, Santacroce R, Margaglione M, Delphin N, Rozet JM, Kaplan J, Martinelli D, Delle Noci N, Soubrane G, Souied EH - Mol. Vis. (2009)

Bottom Line: Six eyes of four patients have been treated for choroidal neovascularization by thermic photocoagulation [one eye], photodynamic therapy [three eyes], and intravitreal ranibizumab injection [two eyes].Mean BCVA impairment showed a statistically significant correlation to a more advanced stage of the disease (p<0.001).BEST1 mutations were not correlated with the severity of the functional and clinical data in the Best VMD patients examined.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Hopital Intercommunal de Creteil, University Paris XII, Paris, France. giuseppe.querques@hotmail.it

ABSTRACT

Purpose: To analyze functional and clinical data of Best vitelliform macular dystrophy (VMD) patients with mutations in the BEST1 gene.

Methods: Best VMD patients with BEST1 mutations were evaluated prospectively regarding age, age of onset, best-corrected visual acuity (BCVA), fundus autofluorescence, fluorescein angiography, optical coherence tomography, and electro-oculography. Mutations in BEST1 were established by direct sequencing.

Results: Forty-six eyes of 23 patients (10 male, 13 female) were included in the study. We identified nine different BEST1 mutations (3/9 novel), in ten unrelated families. The age of patients ranged between 3 and 75 years; age of onset varied between 2 and 67 years. BCVA ranged between 20/20 and 20/200. On the basis of fundus biomicroscopy with direct illumination, using one widely accepted classification, the macular lesions could be counted as follows: 1. no lesion (normal fovea): eight eyes, five patients carrying a mutation on the BEST1 gene; 2. previtelliform lesions: six eyes, three affected patients; 3. vitelliform lesions: four eyes, two affected patients; 4. pseudohypopyon: three eyes, three affected patients; 5. vitelliruptive lesions (scrambled egg aspect with dispersion of the vitelliform material without sign of atrophy or fibrosis): ten eyes, six affected patients; 6. atrophic lesions (atrophy with or without residual dispersed material): seven eyes, five patients; 7. fibrotic lesions: eight eyes, five patients. Two patients presented unilateral Best VMD. Both eyes of two patients presented multifocal Best VMD features on fundus examination. Six eyes of four patients have been treated for choroidal neovascularization by thermic photocoagulation [one eye], photodynamic therapy [three eyes], and intravitreal ranibizumab injection [two eyes]. Comparison of interfamilial and intrafamilial clinical data between patients did not reveal differences in age, BCVA, and stage of the disease as evaluated by fundus autofluorescence, fluorescein angiography, and optical coherence tomography (p>0.05). Mean BCVA impairment showed a statistically significant correlation to a more advanced stage of the disease (p<0.001).

Conclusions: BEST1 mutations were not correlated with the severity of the functional and clinical data in the Best VMD patients examined.

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Related in: MedlinePlus

Protein sequence alignments via Protein Basic Local Alignment Search Tool (BLASTP) of the regions of the human proteins of the BEST family (BEST1–4) and of the BEST1 proteins containing the p.T4A, p.G15D, and p.I230T novel mutations. The residues at position 4, 15, and 230 are highly conserved from mammals to flies as well as in two-thirds of the human BEST proteins. Interestingly, when nonconserved, the amino acids are replaced by residues of the same classes (neutral polar threonine at position 4 is changed to neutral polar asparagine and serine in human BEST4 and worm BEST1 proteins, respectively; nonpolar uncharged glycine at position 15 is changed to uncharged nonpolar phenylalanine in the human BEST3 and worm BEST1 sequences, respectively; neutral nonpolar isoleucine at position 230 is changed to valine in the human BEST3 and worm BEST1 proteins). Interestingly, the three novel BEST1 mutations reported here are expected to change the polarity and/or the charge of the protein. The p.T4A mutation changes a polar to a nonpolar amino acid, while the p.G15D and I230T mutations change nonpolar uncharged residues to polar acidic (aspartic acid) and neutral nonpolar (threonine) residues, respectively.
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f3: Protein sequence alignments via Protein Basic Local Alignment Search Tool (BLASTP) of the regions of the human proteins of the BEST family (BEST1–4) and of the BEST1 proteins containing the p.T4A, p.G15D, and p.I230T novel mutations. The residues at position 4, 15, and 230 are highly conserved from mammals to flies as well as in two-thirds of the human BEST proteins. Interestingly, when nonconserved, the amino acids are replaced by residues of the same classes (neutral polar threonine at position 4 is changed to neutral polar asparagine and serine in human BEST4 and worm BEST1 proteins, respectively; nonpolar uncharged glycine at position 15 is changed to uncharged nonpolar phenylalanine in the human BEST3 and worm BEST1 sequences, respectively; neutral nonpolar isoleucine at position 230 is changed to valine in the human BEST3 and worm BEST1 proteins). Interestingly, the three novel BEST1 mutations reported here are expected to change the polarity and/or the charge of the protein. The p.T4A mutation changes a polar to a nonpolar amino acid, while the p.G15D and I230T mutations change nonpolar uncharged residues to polar acidic (aspartic acid) and neutral nonpolar (threonine) residues, respectively.

Mentions: The screening of the 11 exons encoding BEST1 in ten unrelated families (4/10 from Italy; 6/10 from France; Figure 1) resulted in the identification of nine different missense mutations clustered in exons 2, 4, and 7 (Table 2). Six out of the nine mutations have been previously reported to be common Best VMD mutations (p.A243V, p.R92G, p. R92C, p.T91I, p.R25W, p.V9A). The remaining three changes have not been reported elsewhere (p.T4A, p.G15D, p.I230T; Figure 2) and were absent from 192 control chromosomes. Interspecies Basic Local Alignment Search Tool (BLAST) alignments showed that residues at positions 4, 15, and 230 are conserved in vertebrate and invertebrate species (Figure 3). Simulation for functional changes by a structure homology-based method using the Polyphen program resulted in classifying the p.T4A and p.G15D changes as possibly damaging (position-specific independent counts, PSIC=1.847 and 1.936, respectively, and the p.I230T substitution as probably damaging (I230T; PSIC=2.181).


Functional and clinical data of Best vitelliform macular dystrophy patients with mutations in the BEST1 gene.

Querques G, Zerbib J, Santacroce R, Margaglione M, Delphin N, Rozet JM, Kaplan J, Martinelli D, Delle Noci N, Soubrane G, Souied EH - Mol. Vis. (2009)

Protein sequence alignments via Protein Basic Local Alignment Search Tool (BLASTP) of the regions of the human proteins of the BEST family (BEST1–4) and of the BEST1 proteins containing the p.T4A, p.G15D, and p.I230T novel mutations. The residues at position 4, 15, and 230 are highly conserved from mammals to flies as well as in two-thirds of the human BEST proteins. Interestingly, when nonconserved, the amino acids are replaced by residues of the same classes (neutral polar threonine at position 4 is changed to neutral polar asparagine and serine in human BEST4 and worm BEST1 proteins, respectively; nonpolar uncharged glycine at position 15 is changed to uncharged nonpolar phenylalanine in the human BEST3 and worm BEST1 sequences, respectively; neutral nonpolar isoleucine at position 230 is changed to valine in the human BEST3 and worm BEST1 proteins). Interestingly, the three novel BEST1 mutations reported here are expected to change the polarity and/or the charge of the protein. The p.T4A mutation changes a polar to a nonpolar amino acid, while the p.G15D and I230T mutations change nonpolar uncharged residues to polar acidic (aspartic acid) and neutral nonpolar (threonine) residues, respectively.
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f3: Protein sequence alignments via Protein Basic Local Alignment Search Tool (BLASTP) of the regions of the human proteins of the BEST family (BEST1–4) and of the BEST1 proteins containing the p.T4A, p.G15D, and p.I230T novel mutations. The residues at position 4, 15, and 230 are highly conserved from mammals to flies as well as in two-thirds of the human BEST proteins. Interestingly, when nonconserved, the amino acids are replaced by residues of the same classes (neutral polar threonine at position 4 is changed to neutral polar asparagine and serine in human BEST4 and worm BEST1 proteins, respectively; nonpolar uncharged glycine at position 15 is changed to uncharged nonpolar phenylalanine in the human BEST3 and worm BEST1 sequences, respectively; neutral nonpolar isoleucine at position 230 is changed to valine in the human BEST3 and worm BEST1 proteins). Interestingly, the three novel BEST1 mutations reported here are expected to change the polarity and/or the charge of the protein. The p.T4A mutation changes a polar to a nonpolar amino acid, while the p.G15D and I230T mutations change nonpolar uncharged residues to polar acidic (aspartic acid) and neutral nonpolar (threonine) residues, respectively.
Mentions: The screening of the 11 exons encoding BEST1 in ten unrelated families (4/10 from Italy; 6/10 from France; Figure 1) resulted in the identification of nine different missense mutations clustered in exons 2, 4, and 7 (Table 2). Six out of the nine mutations have been previously reported to be common Best VMD mutations (p.A243V, p.R92G, p. R92C, p.T91I, p.R25W, p.V9A). The remaining three changes have not been reported elsewhere (p.T4A, p.G15D, p.I230T; Figure 2) and were absent from 192 control chromosomes. Interspecies Basic Local Alignment Search Tool (BLAST) alignments showed that residues at positions 4, 15, and 230 are conserved in vertebrate and invertebrate species (Figure 3). Simulation for functional changes by a structure homology-based method using the Polyphen program resulted in classifying the p.T4A and p.G15D changes as possibly damaging (position-specific independent counts, PSIC=1.847 and 1.936, respectively, and the p.I230T substitution as probably damaging (I230T; PSIC=2.181).

Bottom Line: Six eyes of four patients have been treated for choroidal neovascularization by thermic photocoagulation [one eye], photodynamic therapy [three eyes], and intravitreal ranibizumab injection [two eyes].Mean BCVA impairment showed a statistically significant correlation to a more advanced stage of the disease (p<0.001).BEST1 mutations were not correlated with the severity of the functional and clinical data in the Best VMD patients examined.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Hopital Intercommunal de Creteil, University Paris XII, Paris, France. giuseppe.querques@hotmail.it

ABSTRACT

Purpose: To analyze functional and clinical data of Best vitelliform macular dystrophy (VMD) patients with mutations in the BEST1 gene.

Methods: Best VMD patients with BEST1 mutations were evaluated prospectively regarding age, age of onset, best-corrected visual acuity (BCVA), fundus autofluorescence, fluorescein angiography, optical coherence tomography, and electro-oculography. Mutations in BEST1 were established by direct sequencing.

Results: Forty-six eyes of 23 patients (10 male, 13 female) were included in the study. We identified nine different BEST1 mutations (3/9 novel), in ten unrelated families. The age of patients ranged between 3 and 75 years; age of onset varied between 2 and 67 years. BCVA ranged between 20/20 and 20/200. On the basis of fundus biomicroscopy with direct illumination, using one widely accepted classification, the macular lesions could be counted as follows: 1. no lesion (normal fovea): eight eyes, five patients carrying a mutation on the BEST1 gene; 2. previtelliform lesions: six eyes, three affected patients; 3. vitelliform lesions: four eyes, two affected patients; 4. pseudohypopyon: three eyes, three affected patients; 5. vitelliruptive lesions (scrambled egg aspect with dispersion of the vitelliform material without sign of atrophy or fibrosis): ten eyes, six affected patients; 6. atrophic lesions (atrophy with or without residual dispersed material): seven eyes, five patients; 7. fibrotic lesions: eight eyes, five patients. Two patients presented unilateral Best VMD. Both eyes of two patients presented multifocal Best VMD features on fundus examination. Six eyes of four patients have been treated for choroidal neovascularization by thermic photocoagulation [one eye], photodynamic therapy [three eyes], and intravitreal ranibizumab injection [two eyes]. Comparison of interfamilial and intrafamilial clinical data between patients did not reveal differences in age, BCVA, and stage of the disease as evaluated by fundus autofluorescence, fluorescein angiography, and optical coherence tomography (p>0.05). Mean BCVA impairment showed a statistically significant correlation to a more advanced stage of the disease (p<0.001).

Conclusions: BEST1 mutations were not correlated with the severity of the functional and clinical data in the Best VMD patients examined.

Show MeSH
Related in: MedlinePlus