Milenkovic, Andrea and Milenkovic, Vladimir M. and Wetzel, Christian H. and Weber, Bernhard H. F. (2018) BEST1 protein stability and degradation pathways differ between autosomal dominant Best disease and autosomal recessive bestrophinopathy accounting for the distinct retinal phenotypes. HUMAN MOLECULAR GENETICS, 27 (9). pp. 1630-1641. ISSN 0964-6906, 1460-2083
Full text not available from this repository. (Request a copy)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 chloride channel. In contrast, dominant mutations escape ER-associated degradation and are subjected to a slightly delayed post-ER degradation via the endo-lysosomal degradation pathway. As a result, increased formation of a non-functional BEST1 channel occurs due to a roughly equimolar incorporation of normal and mutant BEST1 subunits into the channel complex. Taken together, our data provide insight into the molecular pathways of dominantly and recessively acting BEST1 missense mutations suggesting that the site of subcellular protein quality control as well as the rate and degree of mutant protein degradation are ultimately responsible for the distinct retinal disease phenotypes in BD and ARB.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | VITELLIFORM MACULAR DYSTROPHY; ENDOPLASMIC-RETICULUM; PLASMA-MEMBRANE; QUALITY-CONTROL; PIGMENT EPITHELIUM; SODIUM 4-PHENYLBUTYRATE; MUTANT BESTROPHIN-1; IN-VITRO; MUTATIONS; GENE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 17 Feb 2020 14:12 |
| Last Modified: | 17 Feb 2020 14:12 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14658 |
Actions (login required)
 |
View Item |
