Article

Characterization of mutations in ATP8B1 associated with hereditary cholestasis

Department of Metabolic and Endocrine Diseases, University Medical Center, Utrecht, The Netherlands.
Hepatology (Impact Factor: 11.19). 07/2004; 40(1):27-38. DOI: 10.1002/hep.20285
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
146 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: The liver is the central place for the metabolism of drugs and other xenobiotics. In the liver cell, oxidation and conjugation of compounds take place, and at the same time, bile formation helps in extrusion of these compounds via the biliary route. A large number of transporters are responsible for drug uptake into the liver cell and excretion into bile or efflux to the sinusoidal blood.Areas covered: Genetic variants of these transporters and their transactivators contribute to changes in drug handling and are also responsible for cholestatic syndromes of different severity. This review summarizes the current knowledge regarding the influence of these genetic changes. The review covers progressive hereditary cholestatic syndromes as well as recurrent or transient cholestatic syndromes such as drug-induced liver injury, intrahepatic cholestasis of pregnancy, and benign recurrent intrahepatic cholestasis.Expert opinion: Polymorphisms in transporter genes are frequent. For clinically relevant cholestatic syndromes, it often requires a combination of genetic variants or acquired triggers such as pregnancy or drug treatment. In combination with other pathogenetic aspects, genetic variants in drug transporters may contribute to our understanding of not only cholestatic diseases such as primary sclerosing cholangitis or primary biliary cirrhosis, but also the natural course of chronic liver disease in general.
    Expert Opinion on Drug Metabolism &amp Toxicology 09/2014; 10(11). DOI:10.1517/17425255.2014.963553 · 2.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Deficiency of the phospholipid flippase ATP8B1 causes progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1). Apart from cholestasis, many patients also suffer from diarrhea of yet unknown etiology. Here we have studied the hypothesis that intestinal ATP8B1 deficiency results in bile salt malabsorption as a possible cause of PFIC1/BRIC1 diarrhea. Bile salt transport was studied in ATP8B1-depleted intestinal Caco-2 cells. Apical membrane localization was studied by a biotinylation approach. Fecal bile salt and electrolyte contents were analyzed in stool samples of PFIC1 patients, of whom some had undergone biliary diversion or liver transplantation. Bile salt uptake by the apical sodium-dependent bile salt transporter SLC10A2 was strongly impaired in ATP8B1-depleted Caco-2 cells. The reduced SLC10A2 activity coincided with strongly reduced apical membrane localization, which was caused by impaired apical membrane insertion of SLC10A2. Moreover, we show that endogenous ATP8B1 exists in a functional heterodimer with CDC50A in Caco-2 cells. Analyses of stool samples of post-transplant PFIC1 patients demonstrated that bile salt content was not changed, whereas sodium and chloride concentrations were elevated and potassium levels were decreased. The ATP8B1-CDC50A heterodimer is essential for the apical localization of SLC10A2 in Caco-2 cells. Diarrhea in PFIC1/BRIC1 patients has a secretory origin to which SLC10A2 deficiency may contribute. This results in elevated luminal bile salt concentrations and consequent enhanced electrolyte secretion and/or reduced electrolyte resorption.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 09/2014; 1842(12). DOI:10.1016/j.bbadis.2014.09.003 · 5.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A new section in MEJDD which is aimed to improve chinical decision making by presenting a real patient by an experienced clinician and who discuss the case and provide an evidence base decision making for diagnosis and treatment of patient in daily clinical practice. Recurrent Cholestasis in a 13 Year-old Boy A 13 year-old boy with generalized intermittent pruritis from three years preceding referred to Shariati Hospital for ERCP. His pruritis was aggravated at night and relieved by warm baths. It was associated with jaundice. During the attacks, he had acholic stool and dark urine. The patient had three attacks in the preced-ing years, each of which lasted for about 3-4 months. Associated symptoms were anorexia and mild weight loss (3kg /3 months). All complaints began after an attack of gastroenteritis. Between attacks, the patient was completely asymptomatic with no com-plaints. History of pruritis has many differential diagnoses. Many of these are primary skin disorders such as xerosis, atopic der-matitis, lichen simplex chronicus, and psoriasis, to name a few; this patient had no history of any allergic reaction or skin lesions. 1 Still, drug and allergic history are important and must be assessed. Likewise, some systemic diseases can cause pruri-tis, such as: renal and thyroid diseases, malignancies, multiple sclerosis, infection with human immune deficiency virus (HIV) and iron deficiency anemia. Therefore, it is imperative that a de-tailed history be taken and the necessary workup performed for patients. Another etiology is cholestasis, which looks more plau-sible as it is similarly associated with jaundice, acholic stool, dark urine, is aggravated at night and relieved with warm baths. Itching in cholestasis is typically generalized although it is most severe on the palms and soles. Dry skin, hot and humid weather, and wearing constricting clothes can worsen this type of itching. The pathogenesis of pruritis in cholestasis is incompletely un-derstood, but accumulation of bile acids in the bloodstream can be a probable explanation. On the other hand, absence of pruritis in many patients with elevated bile acids and lack of correlation between pruritis and bile acid concentrations make this hypoth-esis a less approved culprit. Alternatively, leakage of pruritogens into the bloodstream can be another plausible etiology. 2

Full-text (2 Sources)

Download
4 Downloads
Available from
Dec 3, 2014