ATP8B1 – Progressive Familial Intrahepatic Cholestasis Type 1

ATP8B1 encodes the P4-ATPase FIC1, whose biallelic pathogenic variants cause progressive familial intrahepatic cholestasis type 1 (PFIC1), an autosomal recessive cholestatic liver disease characterized by low serum γ-glutamyltransferase and early-onset pruritus and jaundice. PFIC1 inheritance is autosomal recessive. Over 56 unrelated probands have been reported with biallelic ATP8B1 variants, including case series, familial segregation and structural variant studies (PMID:17101580) indicating a definitive gene–disease relationship.

The genetic evidence includes compound heterozygous and homozygous variants segregating with disease in multiple families. In two consanguineous sibships, three affected individuals across two families were homozygous for a novel splice-site mutation leading to exon 16 skipping and a frameshift (PMID:23033845). Case reports describe both missense and truncating alleles, and multi-patient cohort studies have identified additional LoF and structural changes, confirming segregation and high penetrance of biallelic variants.

The ATP8B1 variant spectrum encompasses missense, nonsense, frameshift, splice-site and large deletion/duplication alleles. Notable recurrent or population-specific alleles include the Inuit founder mutation with 12% heterozygote frequency among East Greenland Inuit (PMID:16635913), and three non-recurrent structural variants (g.55396652_55403080del, g.55335906_55346620dup, g.55362063_55364293dup) discovered by whole-genome sequencing in patients with only one coding variant detected by exome sequencing (PMID:34543749).

Functional studies establish loss-of-function as the pathogenic mechanism. ATP8B1 requires CDC50A for ER exit and canalicular localization, and co-expression restores phosphatidylserine flippase activity in cell lines (PMID:17948906). Knock-in Atp8b1(G308V/G308V) mice exhibit progressive hearing loss and canalicular membrane disruption under bile acid challenge (PMID:19478059; PMID:19027009). Pharmacological chaperones such as 4-phenylbutyrate partially rescue folding and membrane localization of common missense mutants (e.g., p.Ile661Thr) in vitro (PMID:19918981).

Some evidence tempers the model: heterozygous carriers (e.g., Greenland Inuit) show no liver phenotype (PMID:16635913), and cholestatic mouse models do not consistently recapitulate pruritus (PMID:33731871). However, these findings do not undermine biallelic LOF causality but highlight species and heterozygous tolerance differences.

In summary, ATP8B1 has a definitive association with PFIC1, supported by over 56 unrelated probands, familial segregation, and concordant mechanistic studies demonstrating flippase deficiency and bile canalicular membrane vulnerability. Genetic testing of ATP8B1 is essential for diagnosis, prognostic stratification in liver transplantation, and therapeutic exploration of proteostasis regulators. Key take-home: Biallelic ATP8B1 variants cause PFIC1 via loss of phospholipid flippase activity, providing clear clinical utility of genetic and functional assays.

References

• Scandinavian Journal of Gastroenterology • 2006 • Geographical clustering and maintained health in individuals harbouring the mutation for Greenland familial cholestasis: A population-based study. PMID:16635913
• Scandinavian Journal of Gastroenterology • 2006 • Normal pancreatic secretion in children with progressive familial intrahepatic cholestasis type 1. PMID:17101580
• Hepatology Communications • 2008 • ATP8B1 requires an accessory protein for endoplasmic reticulum exit and plasma membrane lipid flippase activity. PMID:17948906
• Gastroenterology • 2009 • ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained. PMID:19027009
• Proceedings of the National Academy of Sciences of the United States of America • 2009 • ATP8B1 is essential for maintaining normal hearing. PMID:19478059
• Hepatology (Baltimore, Md.) • 2010 • Folding defects in P-type ATP 8B1 associated with hereditary cholestasis are ameliorated by 4-phenylbutyrate. PMID:19918981
• Journal of Gastroenterology and Hepatology • 2013 • Novel splice-site mutation in ATP8B1 results in atypical progressive familial intrahepatic cholestasis type 1. PMID:23033845
• Journal of Hepatology • 2016 • Rescue of defective ATP8B1 trafficking by CFTR correctors as a therapeutic strategy for familial intrahepatic cholestasis. PMID:26879107
• Journal of Pediatric Gastroenterology and Nutrition • 2021 • Long-term Outcomes of Living-donor Liver Transplantation for Progressive Familial Intrahepatic Cholestasis Type 1. PMID:33264179
• Hepatology Communications • 2021 • Assessment of Adenosine Triphosphatase Phospholipid Transporting 8B1 (ATP8B1) Function in Patients With Cholestasis With ATP8B1 Deficiency by Using Peripheral Blood Monocyte-Derived Macrophages. PMID:33437900
• Scientific Reports • 2021 • Reduced spontaneous itch in mouse models of cholestasis. PMID:33731871
• The Journal of Molecular Diagnostics : JMD • 2021 • Whole-Genome Sequencing Reveals Large ATP8B1 Deletion/Duplications as Second Mutations Missed by Exome-Based Sequencing. PMID:34543749

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