BEST1: the Best Target for Gene and Cell Therapies.
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ABSTRACT:
SUBMITTER: Yang T
PROVIDER: S-EPMC4700113 | biostudies-literature | 2015 Dec
REPOSITORIES: biostudies-literature
Publications
BEST1: the Best Target for Gene and Cell Therapies.
Yang Tingting T Justus Sally S Li Yao Y Tsang Stephen H SH
Molecular therapy : the journal of the American Society of Gene Therapy 20150921 12
A retinal pigmented epithelial (RPE) disorder, bestrophinopathy has recently been proven to be amenable to gene and cell-based therapies in preclinical models. RPE disorders and allied retinal degenerations exhibit significant genetic heterogeneity, and diverse mutations can result in similar disease phenotypes. Several RPE disorders have recently become targets for gene therapies in humans. The year 2011 brought a new advance in cell-based therapies, with the Food and Drug Administration approv ...[more]
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Project description: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.
| S-EPMC2802291 | biostudies-literature
Project description:AIMS: To describe genetic and clinical findings in a French family affected by best vitelliform macular dystrophy (BVMD). METHODS: We screened eight at-risk members of a family, including a BVMD-affected proband, by direct sequencing of 11 bestrophin-1 (BEST1) exons. Individuals underwent ophthalmic examination and autofluorescent fundus imaging, indocyanine green angiography, electro-oculogram (EOG), electroretinogram (ERG), multifocal ERG, optical coherence tomography (OCT), and where possible, spectral domain OCT. RESULTS: The sequence analysis of the BEST1 gene revealed one previously unknown mutation, c.15C>A (p.Y5X), in two family members and one recently described mutation, c.430A>G (p.S144G), in five family members. Fundus examination and electrophysiological responses provided no evidence of the disease in the patient carrying only the p.Y5X mutation. Three patients with the p.S144G mutation did not show any preclinical sign of BVMD except altered EOGs. Two individuals of the family exhibited a particularly severe phenotype of multifocal BVMD-one individual carrying the p.S144G mutation heterozygously and one individual harboring both BEST1 mutations (p.S144G inherited from his mother and p.Y5X from his father). Both of these family members had multifocal vitelliform autofluorescent lesions combined with abnormal EOG, and the spectral domain OCT displayed a serous retinal detachment. In addition, ERGs demonstrated widespread retinal degeneration and multifocal ERGs showed a reduction in the central retina function, which could be correlated with the decreased visual acuity and visual field scotomas. CONCLUSIONS: A thorough clinical evaluation found no pathological phenotype in the patient carrying the isolated p.Y5X mutation. The patients carrying the p.S144G variation in the protein exhibited considerable intrafamilial phenotypic variability. Two young affected patients in this family exhibited an early onset, severe, multifocal BVMD with a diffuse distribution of autofluorescent deposits throughout the retina and rapid evolution toward the loss of central vision. The other genetically affected relatives had only abnormal EOGs and displayed no or extremely slow electrophysiological evolution.
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Project description:Adult-onset vitelliform macular dystrophy (AVMD) is a common and benign macular degeneration which can be caused by BEST1 mutation. Here, we investigated the clinical characteristics associated with a newly identified BEST1 mutation, p.Ile38Ser and confirmed the associated physiological functional defects. The 51-year-old patient presented bilateral small subretinal yellow deposits. Consistent with AVMD, the corresponding lesions showed hyperautofluorescence, late staining in fluorescein angiography, and subretinal hyper-reflective materials in spectral-domain optical coherence tomography. Genetic analysis demonstrated that the patient presented with a heterozygous p.Ile38Ser BEST1 mutation. Surface biotinylation and patch clamp experiments were performed in transfected HEK293T cells. Although, the identified BEST1 mutant maintains normal membrane expression, p.Ile38Ser mutant showed significantly smaller currents than wild type (WT). However, it showed larger currents than other BEST1 mutants, p.Trp93Cys, causing autosomal dominant best vitelliform macular dystrophy (BVMD), and p.Ala195Val, causing autosomal recessive bestrophinopathy (ARB). The cells expressing both WT and each BEST1 mutant showed that the functional defect of p.Ile38ser was milder than that of p.Trp93Cys, whereas combination of p.Ala195Val with WT showed good current. We identified and described the phenotype and in vitro functions of a novel BEST1 mutation causing AVMD. AVMD induced by p.Ile38Ser BEST1 mutation is a mild form of BVMD.
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