Prediction of Functional Consequences of Missense Mutations in ANO4 Gene

• Published in: International journal of molecular sciences Vol. 22; no. 5; p. 2732
• Main Authors: Reichhart, Nadine, Milenkovic, Vladimir M, Wetzel, Christian H, Strauß, Olaf
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 08.03.2021; MDPI AG
• Subjects: Amino Acid Substitution; ANO4 gene; ANO4 protein; Anoctamins - chemistry; Anoctamins - genetics; disease-association; homology model; Humans; Mutation, Missense; Protein Stability; protein structure; Sequence Analysis, Protein; SNP; protein structure; ANO4 protein; ANO4 gene; SNP; molecular dynamics simulation; disease-association; protein stability; homology model
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22052732

The anoctamin (TMEM16) family of transmembrane protein consists of ten members in vertebrates, which act as Ca -dependent ion channels and/or Ca -dependent scramblases. ANO4 which is primarily expressed in the CNS and certain endocrine glands, has been associated with various neuronal disorders. Therefore, we focused our study on prioritizing missense mutations that are assumed to alter the structure and stability of ANO4 protein. We employed a wide array of evolution and structure based in silico prediction methods to identify potentially deleterious missense mutations in the ANO4 gene. Identified pathogenic mutations were then mapped to the modeled human ANO4 structure and the effects of missense mutations were studied on the atomic level using molecular dynamics simulations. Our data show that the G80A and A500T mutations significantly alter the stability of the mutant proteins, thus providing new perspective on the role of missense mutations in ANO4 gene. Results obtained in this study may help to identify disease associated mutations which affect ANO4 protein structure and function and might facilitate future functional characterization of ANO4.