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

ABSTRACT: Mutations in bestrophin-1 (BEST1) are associated with distinct retinopathies, notably three forms with autosomal dominant inheritance and one condition with an autosomal recessive mode of transmission. The molecular mechanisms underlying their distinct retinal phenotypes are mostly unknown. Although heterozygous missense mutations in BEST1 reveal dominant-negative effects in patients with autosomal dominant Best disease (BD), heterozygous mutations associated with autosomal recessive bestrophinopathy (ARB) display no disease phenotype. Here we show that the recessive mutations trigger a strong and fast protein degradation process in the endoplasmic reticulum (ER), thereby favoring a decreased stoichiometry of mutant versus normal BEST1 subunits in the assembly of the homo-pentameric BEST1

SUBMITTER: Milenkovic A 

PROVIDER: S-EPMC5905664 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature