Clinical, Genetics, and Bioinformatic Characterization of Mutations Affecting an Essential Region of PLS3 in Patients with BMND18

Background. Bone mineral density quantitative trait locus 18 (BMND18, OMIM #300910) is a type of early-onset osteogenesis imperfecta (OI) caused by loss-of-function mutations in the PLS3 gene, which encodes plastin-3, a key protein in the formation of actin bundles throughout the cytoskeleton. Here, we report a patient with PLS3 mutation caused BMND18 and evaluated all the reported disease-causing mutations by bioinformatic analysis. Methods. Targeted gene sequencing was performed to find the disease-causing mutation in our patient. Bioinformatic analyses mainly including homology modelling and molecular dynamics stimulation were conducted to explore the impact of the previously reported mutations on plastin-3. Results. Gene sequencing showed a novel nonsense mutation (c.745G > T, p.E249X), which locates at a highly conserved region containing residues p.240–266 (LOOP-1) in the PLS3 gene. Further bioinformatic analyses of the previously reported mutations revealed that LOOP-1 is predicted to physically connect the calponin-homology 1 (CH1) and CH2 domains of the ABD1 fragment and spatially locates within the interface of ABD1 and ABD2. It is crucial to the conformation transition and actin-binding function of plastin-3. Conclusions. This report identified a novel mutation that truncates the PLS3 gene. Moreover, bioinformatic analyses of the previous reported mutations in PLS3 gene lead us to find a critical LOOP-1 region of plastin-3 mutations at which may be detrimental to the integral conformation of plastin-3 and thus affect its binding to actin filament.