Mutations in PIEZO2 contribute to Gordon syndrome, Marden-Walker syndrome and distal arthrogryposis: A bioinformatics analysis of mechanisms.

Piezo type mechanosensitive ion channel component 2 (PIEZO2) is a mechanically activated ion channel. Mutations in PIEZO2 may cause distal arthrogryposis 3 (DA3)/Gordon syndrome (GS), DA5, Marden-Walker syndrome (MWS) and associated diseases. To date, no systematic study has analyzed and compared the influence of different gene mutations of PIEZO2 on its transcription, as well as translation and protein function. Therefore, the objective of the present study was to systematically assess the effect of different pathological mutations of PIEZO2 on transcription, translation, as well as protein structure and function that contribute to GS/DA3, DA5, MWS and associated diseases based on a bioinformatics analysis using the Pubmed, ClinVar, RaptorX and Phyre2 online databases. The results indicated the presence of 27 pathological mutations in PIEZO2, including dominant and recessive mutations. Dominant mutations were mainly located in the C-terminal region, whereas recessive mutations were mainly localized in the N-terminal region, and most reported mutation sites exhibited high evolutionary conservation among different species. Loss-of-function mutations result in nonsense-mediated transcript decay or premature termination codons, consequently leading to a lack of PIEZO2 protein, whereas gain-of-function mutations may lead to increased PIEZO2-associated channel activity. The bioinformatics analysis results also indicated that the p.Ala1486Pro, p.Thr2221Ile and p.Glu2727del mutations modify the secondary structure of the PIEZO2 protein, while p.Thr2221Ile, p.Arg2718Leu and p.Arg2718Pro mutations reduce the solvent accessibility of PIEZO2 protein. Furthermore, the p.Ala1486Pro, p.Thr2221Ile, p.Ser2223Leu, p.Thr2356Met, p.Arg2686His, p.Arg2718Leu, p.Arg2718Pro and p.Glu2727del mutations affect the transmembrane region. These changes of PIEZO2 may contribute to a gain-of-function of PIEZO2. Variable clinical phenotypes were present between and among the gain- and loss-of-function mutations linked with PIEZO2-associated disease, which implied that different mutations in PIEZO2 have different pathophysiological effects. Of course, further functional studies to explore the precise structure and function of PIEZO2 are necessary and may offer useful clues for the prevention and treatment of associated diseases.