Molecular and computational characterization of ABCB11 and ABCG5 variants in Tunisian patients with neonatal/infantile low‐GGT intrahepatic cholestasis: Genetic diagnosis and genotype–phenotype correlation assessment

Abstract

Many inherited conditions cause hepatocellular cholestasis in infancy, including progressive familial intrahepatic cholestasis (PFIC), a heterogeneous group of diseases with highly overlapping symptoms. In our study, six unrelated Tunisian infants with PFIC suspicion were the subject of a panel–target sequencing followed by an exhaustive bioinformatic and modeling investigations. Results revealed five disease‐causative variants including known ones: (the p.Asp482Gly and p.Tyr354 * in the ABCB11 gene and the p.Arg446 * in the ABCC2 gene), a novel p.Ala98Cys variant in the ATP‐binding cassette subfamily G member 5 (ABCG5) gene and a first homozygous description of the p.Gln312His in the ABCB11 gene. The p.Gln312His disrupts the interaction pattern of the bile salt export pump as well as the flexibility of the second intracellular loop domain harboring this residue. As for the p.Ala98Cys, it modulates both the interactions within the first nucleotide‐binding domain of the bile transporter and its accessibility. Two additional potentially modifier variants in cholestasis‐associated genes were retained based on their pathogenicity (p.Gly758Val in the ABCC2 gene) and functionality (p.Asp19His in the ABCG8 gene). Molecular findings allowed a PFIC2 diagnosis in five patients and an unexpected diagnosis of sisterolemia in one case. The absence of genotype/phenotype correlation suggests the implication of environmental and epigenetic factors as well as modifier variants involved directly or indirectly in the bile composition, which could explain the cholestasis phenotypic variability.

Benign Recurrent Intrahepatic Cholestasis: Where Are We Now?

“…The BSEP, a member of the adenosino-triphosphate (ATP)-binding cassette (ABC) transporter family, utilizes ATP to transport substrates, such as taurocholate and other BSs [24][25][26]. Genetic variability is present, evidenced by various mutations in aforementioned genes [18,19,[27][28][29][30][31]. New mutations in ATP8B1, ABCB11, and SLC51A genes have recently been reported [15,18,19,[27][28][29][30].…”

“…Genetic variability is present, evidenced by various mutations in aforementioned genes [18,19,[27][28][29][30][31]. New mutations in ATP8B1, ABCB11, and SLC51A genes have recently been reported [15,18,19,[27][28][29][30]. Notably, over 100 mutations in ABCB11 have been described, with more than 50% being non-sense mutations [28][29][30][31][32].…”

“…New mutations in ATP8B1, ABCB11, and SLC51A genes have recently been reported [15,18,19,[27][28][29][30]. Notably, over 100 mutations in ABCB11 have been described, with more than 50% being non-sense mutations [28][29][30][31][32].…”