Disease relevance of BEST1

• Best macular dystrophy (BMD), also known as vitelliform macular dystrophy (VMD2; OMIM 153700), is an autosomal dominant form of macular degeneration characterized by an abnormal accumulation of lipofuscin within and beneath the retinal pigment epithelium cells [1].
• Mutations in human bestrophin-1 (VMD2) are genetically linked to several forms of retinal degeneration but the underlying mechanisms are unknown [2].
• CONCLUSION: These data confirm the involvement of the VMD2 gene in Best macular dystrophy onset, even in sporadic cases of the disease, pointing out the relevance of molecular analysis in the diagnosis of this degenerative retinal disease [3].
• Do "America's Best Hospitals" perform better for acute myocardial infarction [4]?
• Both DMD and the mild form, Becker muscular dystrophy (BMD), are X-linked [5].

Psychiatry related information on BEST1

• FM and extracellular-to-intracellular-water ratio were measured by bromide-deuterium dilution, BMD by dual-energy x-ray absorptiometry, GH function by fasted serum insulin-like growth factor-I concentration, and physical activity by doubly-labeled water in combination with basal metabolic rate by a ventilated hood [6].
• Change in Lumbar Spine BMD and Vertebral Fracture Risk Reduction in Teriparatide-Treated Postmenopausal Women With Osteoporosis* [7].
• After adjustment for CC, age, weight, alcohol consumption, and cigarette smoking, high PA compared with medium or low PA was associated with higher hip BMD and heel QUS (total hip BMD, 3.1%; p < 0.001; QUS stiffness, 2.7%; p = 0.002) [8].
• INTRODUCTION:: Prevalence estimates of osteopenia and osteoporosis (reduced bone mineral density; BMD) in HIV-infected patients and the role of antiretroviral therapy (ART) varies in the literature [9].
• 1. Best-subset regression analysis and receiver operating characteristic analysis were used to select a subset of items from the structured interview that most efficiently predicted PTSD as diagnosed in the full-length interview [10].

High impact information on BEST1

• Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), a much milder form of the disease where the age of onset can sometimes be as late as the third or fourth decade of life, are caused by mutations in the same X-linked gene, a 14 kilobase (kb) transcript which is spread over more than 2 megabases of the human X chromosome [11].
• Most mutations causing DMD and BMD are deletions and deletions associated with both phenotypes are observed throughout the gene sequence [11].
• This observation led to the suggestion that DMD patients possess deletions that disrupt the reading frame of the protein, whereas BMD patients have deletions that retain the translational reading frame and enable the muscle cells to produce altered dystrophin products [11].
• This theory is supported by immunoblotting studies, which show that DMD patients lack dystrophin in their muscle cells or that dystrophin is present at very low levels, whereas BMD patients produce a protein with reduced abundance or abnormal size [11].
• Here we describe a deletion of the dystrophin gene in a family segregating for very mild BMD, one member of which was still ambulant at age 61 years, which removes a central part of the dystrophin gene encompassing 5,106 base pairs of coding sequence, almost half the coding information [11].

Chemical compound and disease context of BEST1

• Interaction analyses with years since menopause, estrogen status, physical activity, smoking, dietary calcium, vitamin D, and alcohol intake were based on BMD measurements at the hip [12].
• CONCLUSIONS: Oral alendronate increases BMD and increase nonsevere gastrointestinal adverse effects but does not modify the hearing loss in adult patients with osteogenesis imperfecta [13].
• In the univariate analysis, significant interactions were observed between raloxifene treatment and age (p = 0.04), serum triglycerides (p = 0.03), LS BMD (p = 0.08), and diabetes mellitus (p = 0.04) [14].
• 25-Hydroxyvitamin D Deficiency and Diabetes Predict Reduced BMD in Patients With Chronic Kidney Disease [15].
• MATERIALS AND METHODS: This prospectively designed subprotocol (n = 308) of ATAC assessed changes in BMD and bone turnover markers in postmenopausal women with invasive primary breast cancer receiving anastrozole 1 mg/day, tamoxifen 20 mg/day, or combination treatment with both agents for 5 years [16].

Biological context of BEST1

• These studies define the VMD2 promoter region sufficient to drive RPE-specific expression in the eye, identify positive regulatory regions in vitro, and suggest that MITF as well as other E-box binding factors may act as positive regulators of VMD2 expression [17].
• Transient transfection assays using the D407 human RPE cell line with VMD2 promoter/luciferase reporter constructs identified two positive regulatory regions, -585 to -541 bp for high level expression and -56 to -42 bp for low level expression [17].
• Single channel analysis of the S2 bestrophin currents revealed an approximately 2-pS single channel with fast gating kinetics and linear current-voltage relationship [2].
• High-resolution meiotic and physical mapping of the best vitelliform macular dystrophy (VMD2) locus to pericentromeric chromosome 11 [18].
• Best vitelliform macular dystrophy (VMD2) has previously been linked to several microsatellite markers from chromosome 11 [18].

Anatomical context of BEST1

• Vitelliform macular dystrophy (VMD2, Best disease, MIM153700) is an early onset, autosomal, dominant macular degeneration characterized by the deposition of lipofuscin-like material within and below the retinal pigment epithelium (RPE); it is associated with degeneration of the RPE and overlying photoreceptors [19].
• So far, all studies were carried out with whole-cell recordings from plasmid-transfected cultured cells, so it is unclear whether Ca(2+) activates bestrophin through a metabolic mechanism or in a more direct way [20].
• Immunocytochemical staining of macaque and porcine eyes indicated that bestrophin is localized at the basolateral plasma membrane of RPE cells [21].
• The data indicate that the presence of a functional bestrophin may contribute to the basolateral cell conductance in airway epithelial cells [22].
• Total and segmental body composition (fat mass, FM; fat-free mass, FFM; bone mineral density, BMD) were evaluated in 13 sedentary spinal cord injury (SCI) subjects and in 13 able-bodied healthy males (control, C) using dual X-ray absorptiometry (DXA) and skinfold methods [23].

Associations of BEST1 with chemical compounds

• RESULTS: A single T to G transition at nucleotide 663 was identified in one of the VMD2 gene copies of the patient, which results in a Cys to Trp substitution at position 221 in the corresponding protein (C221W) [3].
• Thus, Ca(2+) appears to activate the bestrophin Cl(-) channel without going through a freely diffusible messenger or through protein phosphorylation [20].
• Hydrodynamic properties of porcine bestrophin-1 in Triton X-100 [24].
• METHODS: Patients with VMD2 were imaged with conventional fundus and autofluorescence photography, fluorescein angiography, fundus photography, and optical coherence tomography (OCT) [25].
• Using heterologous expression, we show here that human, Drosophila, and C. elegans bestrophins form oligomeric chloride channels, and that human bestrophin is sensitive to intracellular calcium [26].

Other interactions of BEST1

• MITF knockdown by small interfering RNA (siRNA) in cell culture revealed a strong correlation between MITF and VMD2 mRNA levels [27].
• Best's vitelliform dystrophy (VMD2) maps between D11S903 and PYGM: no evidence for locus heterogeneity [28].
• Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC) [29].
• The data showed that VMD2 mutations caused defects of ocular patterning, supporting the hypothesized role for the RPE, and specifically VMD2, in the normal growth and development of the eye [29].
• Recombination events localized the disease gene to the 5-cM interval D11S956-UGB, a genetic inclusion interval that substantially overlaps the VMD2 inclusion interval defined by recombinants at FCER1B and UGB observed by other research groups [30].

Analytical, diagnostic and therapeutic context of BEST1

• Four individuals who did not have maculopathy, but did have an abnormal EOG, also had mutations in the VMD2 gene [31].
• Sequence analysis of the VMD2 exon 6 of both parents of the patient did not reveal any mutation [3].
• Use of denaturing HPLC and automated sequencing to screen the VMD2 gene for mutations associated with Best's vitelliform macular dystrophy [32].
• Results of transient transfections in two cell lines that constitutively express VMD2 were similar, and results in transgenic mice were consistent, providing validation for promoter analysis by in vivo electroporation [33].
• METHODS: Clinical examination, electrophysiologic assessment, B-scan ultrasonography, and mutation screening of the gene VMD2 [34].

References