The ATP8B1 gene encodes a type-4 P-type cation transport ATPase with phospholipid-translocating ATPase activity. Specifically, the ATP8B1 protein translocates phosphatidylserine and phosphatidylethanolamine from the outer to the inner leaflets of membrane bilayers, thus maintaining lipid homeostasis. The ATPase is also involved in the transport of a mitochondrial membrane phospholipid known as cardiolipin. By carrying out its function, ATP8B1 is involved in bile acid and bile salt transport, bile acid metabolic process, regulation of microvillus assembly and vestibulocochlear nerve formation.
The gene is associated with Cholestasis, Benign Recurrent Intrahepatic, 1 (BRIC1), Cholestasis, Progressive Familial Intrahepatic, 1 (PFIC1) and Cholestasis, Intrahepatic, Of Pregnancy, 1 (ICP1). ICP1 is a reversible form of cholestasis occurring in the third trimester of pregnancy. BRIC1 is a relatively mild condition characterized by intermittent episodes of cholestasis accompanied by pruritis and cholestatic jaundice. PFIC1 is a more severe disorder characterized by short stature, deafness, diarrhea and end stage liver disease.
The ATP8B1 gene is located on the long arm of chromosome 18. It spans a length of 157 kb of DNA and its coding sequence is spread across 29 exons. The protein product encoded by this gene has a molecular mass of 143 kDa and consists of 1251 amino acids. The gene is widely expressed in several tissues but is most abundant in the pancreas and small intestine.
Heterozygous missense mutations in the gene result in the autosomal dominant condition of ICP1 while homozygous and compound heterozygous mutations are associated with the autosomal recessive conditions BRIC1 and PFIC1. Variants linked with BRIC1 are generally missense mutations that result in a moderate alteration in the structure or function of the ATP8B1 gene. Mutations associated with PFIC1 are mainly large deletions or variants that result in an abnormally truncated ATP8B1 protein. So far, more than 50 mutations in ATP8B1 have been associated with PFIC1.