Abstract
Background
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).
Methods
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.
Results
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.
Conclusion
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.
Keywords
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Article info
Publication history
Published online: April 27, 2022
Accepted:
April 4,
2022
Received:
January 11,
2022
Identification
Copyright
© 2022 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
