Abstract
Background: Wilson’s disease (WD) is a genetic disorder involving the metabolism of copper. WD patients exhibit a wide range of disease phenotypes, including Kayser-Fleischer rings in the cornea, predominant progressive hepatic disease, neurological diseases, and/or psychiatric illnesses, among others. Patients with exon12 mutations of the ATP7B gene have progressive hepatic disease. An ATP7B gene that lacks exon12 retains 80% of its copper transport activities, suggesting that alternative splicing of ATP7B gene may provide alternative therapeutic ways for patients with inherited sequence variants and mutations of this gene. Purpose: We aimed to search for possible Chinese herbs and related compounds for modulating ATP7B premRNA splicing. Methods: We used an ATP7B exon11-12-13 mini-gene vector as a model and screened 18 Chinese herbal extracts and four compounds from Schizonepeta to determine their effects on ATP7B pre-mRNA splicing in vitro. Results: We found that Schizonepeta demonstrated the greatest potential for alternative splicing activity. Specifically, we found that p-coumaric acid from this herb enhanced ATP7B exon12 exclusion through the down-regulation of heterogeneous ribonucleoprotein (hnRNP) A1 protein expressions. Conclusion: These results suggest that there are herbs or herb-related compounds that could modify the alternative splicing of the ATP7B gene via a mechanism that regulates pre-mRNA splicing.
Highlights
Wilson’s disease (WD; MIM number: 277900) is a genetic disorder involving the metabolism of copper [1, 2]
Results from HPLC analyses indicated the presence of apigenin, luteolin, caffeic acid, and p-coumaric acid in our Schizonepeta water extract (Fig. 2)
These results indicated the presence of apigenin, luteolin, caffeic acid and p-coumaric acid in our Schizonepeta water extract
Summary
Wilson’s disease (WD; MIM number: 277900) is a genetic disorder involving the metabolism of copper [1, 2]. Patients with WD exhibit a wide range of disease phenotypes, including Kayser-Fleischer rings in the cornea, predominant progressive hepatic disease, neurological diseases, and/or psychiatric illnesses, among others [3] These phenotypes can present as early as 3 years of age up to as late as the seventh decade of a person’s life. WD patients exhibit a wide range of disease phenotypes, including Kayser-Fleischer rings in the cornea, predominant progressive hepatic disease, neurological diseases, and/or psychiatric illnesses, among others. Conclusion: These results suggest that there are herbs or herb-related compounds that could modify the alternative splicing of the ATP7B gene via a mechanism that regulates pre-mRNA splicing
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