Could Dissimilar Phenotypic Effects of ACTB Missense Mutations Reflect the Actin Conformational Change Two Novel Mutations and Literature Review

Abstract

The beta-actin gene encodes 1 of 6 different actin proteins. De novo heterozygous missense mutations in <i>ACTB </i>have been identified in patients with Baraitser-Winter syndrome (BRWS) and also in patients with developmental disorders other than BRWS, such as deafness, dystonia, and neutrophil dysfunction. We describe 2 different novel de novo missense <i>ACTB </i>mutations, c.208C>G (p.Pro70Ala) and c.511C>T (p.Leu171Phe), found by trio exome sequencing analysis of 2 unrelated patients: an 8-year-old boy with a suspected BRWS and a 4-year-old girl with unclear developmental disorder. The mutated residue in the first case is situated in the actin H-loop, which is involved in actin polymerization. The mutated residue in the second case (p.Leu171Phe) is found at the actin barbed end in the W-loop, important for binding to profilin and other actin-binding molecules. While the boy presented with a typical BRWS facial appearance, the girl showed facial features not recognizable as a BRWS gestalt as well as ventricular arrhythmia, cleft palate, thrombocytopenia, and gray matter heterotopia. We reviewed previously published <i>ACTB </i>missense mutations and ascertained that a number of them do not cause typical BRWS. By comparing clinical and molecular data, we speculate that the phenotypic differences found in <i>ACTB </i>missense mutation carriers might supposedly be dependent on the conformational change of <i>ACTB</i>.