BEST1 protein stability and degradation pathways differ between autosomal dominant Best disease and autosomal recessive bestrophinopathy accounting for the distinct retinal phenotypes

摘要: Mutations in bestrophin-1 (BEST1) are associated with distinct retinopathies, notably three forms autosomal dominant inheritance and one condition an recessive mode of transmission. The molecular mechanisms underlying their retinal phenotypes mostly unknown. Although heterozygous missense mutations BEST1 reveal dominant-negative effects patients Best disease (BD), bestrophinopathy (ARB) display no phenotype. Here we show that the trigger a strong fast protein degradation process endoplasmic reticulum (ER), thereby favoring decreased stoichiometry mutant versus normal subunits assembly homo-pentameric chloride channel. In contrast, escape ER-associated subjected to slightly delayed post-ER via endo-lysosomal pathway. As result, increased formation non-functional channel occurs due roughly equimolar incorporation into complex. Taken together, our data provide insight pathways dominantly recessively acting suggesting site subcellular quality control as well rate degree ultimately responsible for BD ARB.