Zheng YF, Weng YH, Li SX, Yang YF. Two novel intronic variants in ABCB4: Clinical features, molecular mechanisms, and literature review. World J Gastroenterol 2026; 32(26): 119398 [DOI: 10.3748/wjg.v32.i26.119398]
Corresponding Author of This Article
Yong-Feng Yang, PhD, Professor, Department of Hepatology, The Second Hospital of Nanjing, The Affiliated to Nanjing University of Chinese Medicine, The Affiliated to Southeast University Medical School, No. 1 Zhongfu Road, Gulou District, Nanjing 210003, Jiangsu Province, China. yangyongfeng@njucm.edu.cn
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Gastroenterology & Hepatology
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research-article
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Zheng YF, Weng YH, Li SX, Yang YF. Two novel intronic variants in ABCB4: Clinical features, molecular mechanisms, and literature review. World J Gastroenterol 2026; 32(26): 119398 [DOI: 10.3748/wjg.v32.i26.119398]
World J Gastroenterol. Jul 14, 2026; 32(26): 119398 Published online Jul 14, 2026. doi: 10.3748/wjg.v32.i26.119398
Two novel intronic variants in ABCB4: Clinical features, molecular mechanisms, and literature review
Yu-Feng Zheng, Yu-Hang Weng, Shun-Xin Li, Yong-Feng Yang
Yu-Feng Zheng, Yu-Hang Weng, Yong-Feng Yang, Department of Hepatology, The Second Hospital of Nanjing, The Affiliated to Nanjing University of Chinese Medicine, The Affiliated to Southeast University Medical School, Nanjing 210003, Jiangsu Province, China
Shun-Xin Li, Clinical Research Center, Department of Hepatology, The Second Hospital of Nanjing, The Affiliated to Nanjing University of Chinese Medicine, The Affiliated to Southeast University Medical School, Nanjing 210003, Jiangsu Province, China
Co-first authors: Yu-Feng Zheng and Yu-Hang Weng.
Author contributions: Zheng YF and Yang YF designed the study; Zheng YF and Weng YH as co-first authors, they played pivotal and indispensable roles in collecting the clinical data, performing the experiments, acquiring and analyzed the data, and interpreting the data; Li SX helped with the experiments; Zheng YF wrote the manuscript; Weng YH and Yang YF revised the manuscript; all authors approved the final version of the article.
Supported by the National Natural Science Foundation of China, No. 81970454.
Institutional review board statement: This study was approved by the Medical Ethics Committee of Nanjing Hospital Affiliated to Nanjing University of Traditional Chinese Medicine (No. 2021-LY-kt052).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: All the available data can be found in the manuscript or Supplementary material.
Corresponding author: Yong-Feng Yang, PhD, Professor, Department of Hepatology, The Second Hospital of Nanjing, The Affiliated to Nanjing University of Chinese Medicine, The Affiliated to Southeast University Medical School, No. 1 Zhongfu Road, Gulou District, Nanjing 210003, Jiangsu Province, China. yangyongfeng@njucm.edu.cn
Received: January 27, 2026 Revised: February 22, 2026 Accepted: March 13, 2026 Published online: July 14, 2026 Processing time: 152 Days and 19.6 Hours
Abstract
BACKGROUND
Multidrug resistance protein 3 (MDR3) is expressed in the capillary duct membranes of liver cells and functions in the transport of phospholipids. ABCB4 variants can cause defects in the expression and function of MDR3. Intronic variants of ABCB4 may cause the aberrant deletion or retention of introns in the open reading frame, thereby affecting the normal expression of MDR3. Although numerous studies on the mechanisms of ABCB4 missense variants have been conducted, research on intronic variants remains scarce.
AIM
To explore the pathogenicity of two newly discovered intronic variants of ABCB4.
METHODS
In 2018-2021, two patients with two novel ABCB4 intronic variants were enrolled and their clinical characteristics were analyzed. The Hospital’s Ethical Review Board approved the study and informed consent was obtained. The pathogenicity of the intronic variants was predicted and analyzed in silico. Minigene analysis was performed to investigate their effects on splicing patterns, and their effects on ABCB4 messenger RNA (mRNA) expression and MDR3 expression were explored. Data were evaluated using t-tests. A literature review of ABCB4 intronic variants was conducted.
RESULTS
The main clinical manifestation in both patients was cholestasis. Liver pathology analysis showed bile duct damage, inflammation, and fibrosis that differed between the patients. Three different pathogenicity prediction tools showed similar results, suggesting that these variants interfere with normal splicing. Minigene experiments demonstrated that c.537-32G>T creates a new alternative intron-splicing receptor, resulting in the retention of a 16-bp intronic sequence. The c.833+2T>C mutation created an alternative intron-splicing donor, resulting in the retention of a 67-bp intronic sequence. Neither variant greatly affected mRNA expression (P < 0.05), but MDR3 expression was downregulated by both (P < 0.05). Literature on ABCB4 intronic variants remains limited, and research into the in vitro pathogenic mechanisms of ABCB4 intron variants is especially scarce.
CONCLUSION
The c.537-32G>T and c.833+2T>C variants of ABCB4 are splicing variants, with 3’ and 5’ splicing sites, respectively. Clinical data, bioinformatic predictions, and in vitro experiments indicate that both are pathogenic.
Core Tip: This study focuses on two rare ABCB4 intronic variants identified in a clinic through gene sequencing. The clinical characteristics of the patients mainly were cholestasis. And the variants were predicted in silico tools which showed pathogenic. Through literature review, we found two intron variants have not been reported, and there is little research on intron variants. In vitro experiments confirmed that both variants lead to intron retention. These two variants have little effect on ABCB4 messenger RNA and both downregulate multidrug resistance protein 3 expression. Which can explain the clinical pathogenicity of the two cases.
