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We recently reported that the intronic splice-site mutation IVS3-8G&gt;A of  CHRNA1  that encodes the muscle nicotinic acetylcholine receptor α subunit disrupts binding of a splicing repressor, hnRNP H. This, in turn, results in exclusive inclusion of the downstream exon P3A. The P3A(+) transcript encodes a non-functional α subunit that comprises 50% of the transcripts in normal human skeletal muscle, but its functional significance remains undetermined. In an effort to search for a potential therapy, we screened off-label effects of 960 bioactive chemical compounds and found that tannic acid ameliorates the aberrant splicing due to IVS3-8G&gt;A but without altering the expression of hnRNP H. Therefore, we searched for another splicing  trans -factor. We found that the polypyrimidine tract binding protein (PTB) binds close to the 3′ end of  CHRNA1  intron 3, that PTB induces skipping of exon P3A and that tannic acid increases the expression of PTB in a dose-dependent manner. Deletion assays of the PTB promoter region revealed that the tannic acid-responsive element is between positions −232 and −74 from the translation initiation site. These observations open the door to the discovery of novel therapies based on PTB overexpression and to detecting possible untoward effects of the overexpression.

human molecular genetics

Tannic acid facilitates expression of the polypyrimidine tract binding protein and alleviates deleterious inclusion of  CHRNA1  exon P3A due to an hnRNP H-disrupting mutation in congenital myasthenic syndrome