Folding defects in P-type ATP 8B1 associated with hereditary cholestasis are ameliorated by 4-phenylbutyrate.

[benign recurrent intrahepatic cholestasis]

Deficiency in P-type ATP 8 B 1 is a severe and clinically highly variable hereditary disorder that is primarily characterized by intrahepatic cholestasis . It presents either as a progressive (progressive familial intrahepatic cholestasis type 1 [PFIC 1 ]) or intermittent (benign recurrent intrahepatic cholestasis type 1 [BRIC 1 ]) disease . ATP 8 B 1 deficiency is caused by autosomal recessive mutations in the gene encoding ATP 8 B 1 , a putative aminophospholipid-translocating P-type adenosine triphosphatase . The exact pathogenesis of the disease is elusive , and no effective pharmacological therapy is currently available . Here , the molecular consequences of six distinct ATP 8 B 1 missense mutations (p .L 127 P , p .G 308 V , p .D 454 G , p .D 554 N , p .I 661 T , and p .G 1040 R ) and one nonsense mutation (p .R 1164 X ) associated with PFIC 1 and /or BRIC 1 were systematically characterized . Except for the p .L 127 P mutation , all mutations resulted in markedly reduced ATP 8 B 1 protein expression , whereas messenger RNA expression was unaffected . Five of seven mutations resulted in (partial ) retention of ATP 8 B 1 in the endoplasmic reticulum . Reduced protein expression was partially restored by culturing the cells at 30 degrees C and by treatment with proteasomal inhibitors , indicating protein misfolding and subsequent proteosomal degradation . Protein misfolding was corroborated by predicting the consequences of most mutations onto a homology model of ATP 8 B 1 . Treatment with 4 -phenylbutyrate , a clinically approved pharmacological chaperone , partially restored defects in expression and localization of ATP 8 B 1 substitutions G 308 V , D 454 G , D 554 N , and in particular I 661 T , which is the most frequently identified mutation in BRIC 1 .A surprisingly large proportion of ATP 8 B 1 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 intermittent (BRIC 1 ) disease .

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Diseases presenting "approved pharmacological chaperone, partially restored defects in expression" symptom

benign recurrent intrahepatic cholestasis

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