Mutation specific drug therapy for progressive familial or benign recurrent intrahepatic cholestasis: A new tool in a near future?

Abstract

COMMENTARY ON: Folding defects in P-type ATP 8B1 associated with hereditary cholestasis are ameliorated by 4-phenylbutyrate. van der Velden LM, Stapelbroek JM, Krieger E, van den Berghe PVE, Berger R, Verhulst PM, Holthuis JCM, Houwen RHJ, Klomp LWJ, van de Graaf SFJ. Hepatology 2010;51:286-296. Copyright 2010. Abstract reprinted with permission of John Wiley and Sons, Inc. www.ncbi.nlm.nih.gov/pubmed/19918981 Abstract: Deficiency in P-type ATP8B1 is a severe and clinically highly variable hereditary disorder that is primarily characterized by intrahepatic cholestasis. It presents either as a progressive (pro- gressive familial intrahepatic cholestasis type 1 (PFIC1)) or intermit- tent (benign recurrent intrahepatic cholestasis type 1 (BRIC1)) disease. ATP8B1 deficiency is caused by autosomal recessive mutations in the gene encoding ATP8B1, a putative aminophospho- lipid-translocating P-type adenosine triphosphatase. The exact path- ogenesis of the disease is elusive, and no effective pharmacological therapy is currently available. Here, the molecular consequences of six distinct ATP8B1 missense mutations (p.L127P, p.G308V, p.D454G, p.D554N, p.I661T, and p.G1040R) and one nonsense muta- tion (p.R1164X) associated with PFIC1 and/or BRIC1 were systemat- ically characterized. Except for the p.L127P mutation, all mutations resulted in markedly reduced ATP8B1 protein expression, whereas messenger RNA expression was unaffected. Five out of seven mutations resulted in (partial) retention of ATP8B1 in the endoplasmic reticulum. Reduced protein expression was partially restored by culturing the cells at 30 C and by treatment with proteasomal inhibitors, which indicates protein misfolding and subsequent proteosomal degrada- tion. Protein misfolding was corroborated by predicting the conse- quences of most mutations onto a homology model of ATP8B1. Treatment with 4-phenylbutyrate, a clinically approved pharmacolog- ical chaperone, partially restored defects in expression and localization of ATP8B1 substitutions G308V, D454G, D554N, and in particular I661T, which is the most frequently identified mutation in BRIC1. Conclusion: A surprisingly large proportion of ATP8B1 mutations resulted in aberrant folding and decreased expression at the plasma membrane. These effects were partially restored by treatment with 4-phenylbutyrate. We propose that treatment with pharmacological chaperones may represent an effective therapeutic strategy to ameliorate the recurrent attacks of cholestasis in patients with inter- mittent (BRIC1) disease.