A novel compound heterozygous mutation in ABCB4 gene in a pedigree with progressive familial intrahepatic cholestasis 3: a case report

Abstract

Progressive familial intrahepatic cholestasis (PFIC) includes a group of genetic autosomal recessive disorders that predominantly affects young children and results in early-onset progressive liver damage. Variations in ABCB4 have been shown to cause PFIC3. However, the association between ABCB4 genotype and clinical manifestations remains unclear. We investigated the clinical manifestations and genetic features of a Chinese Han pedigree with PFIC3. A 15-year-old boy, with high-serum gamma-glutamyl transferase (γ-GT) cholestatic cirrhosis, was diagnosed with PIFC3. After ursodeoxycholic acid (UDCA) treatment, the boy stayed in a relatively stable state with mild itching, and elevated γ-GT exhibited a remarkable decrease. Genetic testing identified a novel compound heterozygous mutation L842P/V1051A in ABCB4, which was inherited from his mother and father, respectively. Several predictive software suggested that these two mutations are pathogenic. Interestingly, the same compound heterozygous mutation was also found in his two sisters, one of whom had a history of intrahepatic cholestasis of pregnancy (ICP) and the other had asymptomatic gallstones. Therefore, this novel compound heterozygous mutation L842P/V1051A caused a continuum of ABCB4-related diseases including ICP, cholelithiasis and PFIC3 in our pedigree. The inconsistency between genotypes and phenotypes may be influenced by other factors. Genetic testing will be useful for diagnosis and genetic counseling.

Keywords: ABCB4; Liver cirrhosis; Progressive familial intrahepatic cholestasis (PFIC); case report; compound heterozygous mutation.

Figure 1

The imaging examination revealed liver cirrhosis, splenomegaly, collateral access and portal vein stenosis. (A) Contrast-enhanced CT shows liver cirrhosis, splenomegaly (blue arrow), and collateral pathway (red arrow); (B) the reconstructed MIP image shows splenomegaly (blue arrow) and the portal vein is about 8 mm in diameter.

Figure 2

The gastroscopy reveals severe esophagogastric varices. (A) Esophagus; (B) cardia; (C) fundus of stomach; (D) body of stomach; (E) antrum of stomach; (F) descending part of duodenum. The esophagogastric varices are indicated by red arrow.

Figure 3

The liver histopathology reveals biliary cirrhosis. (A) Cirrhosis demonstrated by Masson trichome staining (Masson trichome 100×); (B) Ductopenia and ductular reaction (Immunostaining for CK-7, 100×); (C) Cholate stasis and formation of Mallory-Denk bodies (red arrow) (H&E 400×); (D) Copper accumulation (Rhodanine 200×) in periseptal liver cells.

Figure 4

Pedigree chart of the patient’s family. The arrow indicates the patient. PFIC3, progressive familial intrahepatic cholestasis; ICP, intrahepatic cholestasis of pregnancy.

Figure 5

Sanger sequencing reveals two heterozygous mutations in ABCB4 gene, c.T2525C(p.L842P) and c.T3152C(p.V1051A).

Figure 6

3D structure of ABCB4. (A) Wild-type; (B) mutant type, (1) for c.T2525C(p.L842P) and (2) for c.T3152C(p.V1051A). The structure of ABCB4 was obtained from Protein Data Bank (Primary Citation of Related Structures: 6S7P). And the mutant structures of ABCB4 were constructed by SWISS-MODEL (https://swissmodel.expasy.org/interactive). Molecular graphics were analyzed by Swiss-Pdb Viewer 4.1.0 software.