[VMD2 and its role in Best's disease and other retinopathies].
Best's vitelliform macular dystrophy (Best's disease) is an autosomal dominant disease of the central retina and is caused by mutations in the VMD2 gene located on the long arm of chromosome 11. VMD2 encodes bestrophin, a transmembrane protein with putative Ca(2+)-dependent chloride channel activity at the basolateral portion of the retinal pigment epithelium. The N-terminal half of bestrophin reveals high sequence homology to three bestrophin-like proteins in humans but also to protein sequences from evolutionarily distant organisms. Most of the known VMD2 mutations are located within this presumably important functional part of the protein and cause amino acid substitutions and small in-frame deletions of single amino acid residues. The pathogenicity of VMD2 mutations is likely based on a dominant negative effect possibly by oligomerization of normal and mutated bestrophin molecules to form a defective ion channel. Missense mutations in VMD2 were also shown to be associated with vitreoretinochoroidopathy and ocular developmental abnormalities. In this case, the pathogenic sequence changes influence the peptide sequences but simultaneously alter the regulation of mRNA splicing and maturation. Different disease mechanisms may therefore be responsible for the distinct phenotypes associated with VMD2 mutations.
Stöhr
H
H
Institut für Humangenetik, Biozentrum der Bayerischen Julius-Maximilians Universität, Würzburg.
Milenkowic
V
V
Weber
B H F
BH
D000075002:Bestrophins; D015415:Biomarkers / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11; D003317:Corneal Dystrophies, Hereditary / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008268:Macular Degeneration / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D012164:Retinal Diseases / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D013329:Structure-Activity Relationship
C113133:BEST1 protein, human; D000075002:Bestrophins; D015415:Biomarkers; D018118:Chloride Channels; D005136:Eye Proteins