Antisense oligonucleotides rescue an intronic splicing variant in the ABCB11 gene that causes progressive familial intrahepatic cholestasis type 2.

Yucan Zheng, Chunlei Zhou, Bixia Zheng, Guorui Hu, Chunli Wang, Wei Zhou, Yan Lu, Zhihua Zhang, Qian Lin, Hongmei Guo, Yu Jin, Zhifeng Liu, Weibing Tang

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2022 Nov

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Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare disorder caused by variants in the ABCB11 gene encoding the bile salt export pump (BSEP). We investigated the molecular defect in a PFIC2 infant and rescued the splicing defect with antisense oligonucleotides (ASOs). Whole-exome sequencing (WES) revealed compound heterozygous variants in the ABCB11 gene in a PFIC2 patient. Liver biopsy was immunostained for BSEP. The splicing effect of the candidate variants was investigated by minigene assay. ASOs were designed to rescue aberrant splicing. A Chinese girl of two nonconsanguineous healthy parents suffered from low glutamyl transpeptidase cholestasis and showed no response to the ursodeoxycholic acid. WES revealed that the patient was compound heterozygous for two novel variants in the ABCB11 gene: c.76+29T>G and c.390-2A>G. Liver immunohistochemistry showed the absence of BSEP. The variant c.76+29T>G was confirmed to retain 42 bp in the mature mRNA. The variant c.390-2A>G was confirmed to cause exon 6 skipping. We designed two ASOs and identified one of them that efficiently induced pseudoexon exclusion. We reported two novel variants of the ABCB11 gene, c.76+29T>G and c.390-2A>G, in a PFIC2 infant, thereby expanding the genotype of PFIC2. Our findings provide evidence for ASOs as a therapeutic approach for PFIC2 patients carrying intronic variants. Copyright © 2022. Published by Elsevier Ltd.

Citation

Yucan Zheng, Chunlei Zhou, Bixia Zheng, Guorui Hu, Chunli Wang, Wei Zhou, Yan Lu, Zhihua Zhang, Qian Lin, Hongmei Guo, Yu Jin, Zhifeng Liu, Weibing Tang. Antisense oligonucleotides rescue an intronic splicing variant in the ABCB11 gene that causes progressive familial intrahepatic cholestasis type 2. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2022 Nov;54(11):1541-1547