Characterization of mutations in ATP8B1 associated with hereditary cholestasis

Department of Psychiatry, University of California, San Francisco, San Francisco, California, United States
Hepatology (Impact Factor: 11.06). 07/2004; 40(1):27-38. DOI: 10.1002/hep.20285
Source: PubMed


Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are clinically distinct hereditary disorders. PFIC patients suffer from chronic cholestasis and develop liver fibrosis. BRIC patients experience intermittent attacks of cholestasis that resolve spontaneously. Mutations in ATP8B1 (previously FIC1) may result in PFIC or BRIC. We report the genomic organization of ATP8B1 and mutation analyses of 180 families with PFIC or BRIC that identified 54 distinct disease mutations, including 10 mutations predicted to disrupt splicing, 6 nonsense mutations, 11 small insertion or deletion mutations predicted to induce frameshifts, 1 large genomic deletion, 2 small inframe deletions, and 24 missense mutations. Most mutations are rare, occurring in 1-3 families, or are limited to specific populations. Many patients are compound heterozygous for 2 mutations. Mutation type or location correlates overall with clinical severity: missense mutations are more common in BRIC (58% vs. 38% in PFIC), while nonsense, frameshifting, and large deletion mutations are more common in PFIC (41% vs. 16% in BRIC). Some mutations, however, lead to a wide range of phenotypes, from PFIC to BRIC or even no clinical disease. ATP8B1 mutations were detected in 30% and 41%, respectively, of the PFIC and BRIC patients screened.

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Available from: Carlos Pabón Peña, Dec 03, 2014
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    • "The c.1587–89del (p.F529del) mutation has been reported previously in European PFIC1 patients of Caucasian descent [19]. Although no other mutations were found in ATP8B1 on the other allele, as was the case for several PFIC1 patients reported in a previous study [19], both patients were diagnosed with PFIC1 because they exhibited the typical clinical symptoms of PFIC1 and because of the low mRNA expression and no detectable protein expression of ATP8B1 in their liver biopsy specimens (Figure  1A, B). The near absence and marked decrease of hepatic ATP8B1 mRNA in patients 1 and 2 may be explained by other mutations in the promoter region and/or untranslated region (UTR) of ATP8B1 on the other allele that affect transcription of ATP8B1 and/or stabilization of ATP8B1 mRNA. "
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    ABSTRACT: Background Progressive familial intrahepatic cholestasis type 1 (PFIC1), an inherited liver disease caused by mutations in ATP8B1, progresses to severe cholestasis with a sustained intractable itch. Currently, no effective therapy has been established for PFIC1. Decreased function of the bile salt export pump (BSEP) in hepatocytes is suggested to be responsible for the severe cholestasis observed in PFIC1. We found a previously unidentified pharmacological effect of 4-phenylbutyrate (4PB) that increases the expression and function of BSEP. Here, we tested 4PB therapy in three patients with PFIC1. Methods The therapeutic potency of 4PB in these patients was tested by oral administration of this drug with gradually increasing dosage (200, 350, and 500 mg/kg/day) for 6 months. Biochemical, histological, and clinical data were collected. Results 4PB therapy had no beneficial effect on the patients’ liver functions, as assessed by biochemical and histological analyses, despite an increase in hepatic BSEP expression. However, therapy with 4PB at a dosage of 350 or 500 mg/kg/day significantly relieved the intractable itch. Serum levels of potential pruritogens in cholestasis were much higher than the reference ranges during the 4PB therapy. Conclusions 4PB therapy may be a new medication for patients with intractable cholestatic pruritus and may improve quality of life for patients and their families.
    Full-text · Article · Jul 2014 · Orphanet Journal of Rare Diseases
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    • "Yet these two CP patients did not have any signs of liver disease or extrahepatic features of ATP8B1 deficiency other than pancreatitis. ATP8B1 deficiency without liver disease has been described before, suggesting that reduced penetrance of the liver phenotype can indeed be seen [15]. Other factors as modifier genes and environmental factors may also contribute to this phenomenon. "
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    ABSTRACT: Mutations in genes encoding cationic trypsinogen (PRSS1), pancreatic secretory trypsin inhibitor (SPINK1) and chymotrypsinogen C (CTRC) are associated with chronic pancreatitis. However, in many patients with a familial chronic pancreatitis pattern suggesting a genetic cause, no mutations in either of these genes can be found, indicating that other, still unknown, associated genes exist. In this respect ATP8B1 is an interesting candidate due to its strong expression in the pancreas, its supposed general function in membrane organization and the higher incidence of pancreatitis in patients with ATP8B1 deficiency. We analyzed all 27 ATP8B1 coding exons and adjacent non-coding sequences of 507 chronic pancreatitis patients by direct sequencing. Exons that harbored possible relevant variations were subsequently sequenced in 1,027 healthy controls. In the exonic regions, 5 novel non-synonymous alterations were detected as well as 14 previously described alterations of which some were associated with ATP8B1 deficiency. However, allele frequencies for any of these variations did not significantly differ between patients and controls. Furthermore, several non-synonymous variants were exclusively detected in control subjects and multiple variants in the non-coding sequence were identified with similar frequencies in both groups. We did not find an association between heterozygous ATP8B1 variants and chronic pancreatitis in our cohort of patients with hereditary and idiopathic chronic pancreatitis.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "Mutations in one of the human members of this subfamily, ATP8B1, give rise to the rare autosomal recessive diseases progressive familial intrahepatic cholestasis (PFIC12 or Byler disease) and the related but less severe benign recurrent intrahepatic cholestasis (BRIC1) [10]. These diseases result in defects in bile salt secretion in the liver canaliculi, leading to episodes of jaundice and severe pruritus, together with non-hepatic symptoms that can include growth defects, diarrhea, and hearing loss [45]. ATP8B1 is expressed in several epithelial tissues and, notably, in the canalicular membrane of the liver [28] and the stereocilia membrane in hair cells [83]. "
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    ABSTRACT: Cellular membranes, notably eukaryotic plasma membranes, are equipped with special proteins that actively translocate lipids from one leaflet to the other and thereby help generate membrane lipid asymmetry. Among these ATP-driven transporters, the P4 subfamily of P-type ATPases (P4-ATPases) comprises lipid flippases that catalyze the translocation of phospholipids from the exoplasmic to the cytosolic leaflet of cell membranes. While initially characterized as aminophospholipid translocases, recent studies of individual P4-ATPase family members from fungi, plants, and animals show that P4-ATPases differ in their substrate specificities and mediate transport of a broader range of lipid substrates, including lysophospholipids and synthetic alkylphospholipids. At the same time, the cellular processes known to be directly or indirectly affected by this class of transporters have expanded to include the regulation of membrane traffic, cytoskeletal dynamics, cell division, lipid metabolism, and lipid signaling. In this review, we will summarize the basic features of P4-ATPases and the physiological implications of their lipid transport activity in the cell.
    Full-text · Article · Sep 2013 · Pflügers Archiv - European Journal of Physiology
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