Differential effects of progressive familial intrahepatic cholestasis type 1 and benign recurrent intrahepatic cholestasis type 1 mutations on canalicular localization of ATP8B1.

[benign recurrent intrahepatic cholestasis]

Mutations in ATP 8 B 1 cause progressive familial intrahepatic cholestasis type 1 (PFIC 1 ) and benign recurrent intrahepatic cholestasis type 1 (BRIC 1 ), forming a spectrum of cholestatic disease . Whereas PFIC 1 is a progressive , endstage liver disease , BRIC 1 patients suffer from episodic periods of cholestasis that resolve spontaneously . At present it is not clear how the type and location of the mutations relate to the clinical manifestations of PFIC 1 and BRIC 1 . ATP 8 B 1 localizes to the canalicular membrane of hepatocytes where it mediates the inward translocation of phosphatidylserine . ATP 8 B 1 interacts with CDC 50 A , which is required for endoplasmic reticulum exit and plasma membrane localization . In this study we analyzed a panel of missense mutations causing PFIC 1 (G 308 V , D 554 N , G 1040 R ) or BRIC 1 (D 70 N , I 661 T ). In addition , we included two mutations that have been associated with intrahepatic cholestasis of pregnancy (ICP ) (D 70 N , R 867 C ). We examined the effect of these mutations on protein stability and interaction with CDC 50 A in Chinese hamster ovary cells , and studied the subcellular localization in WIF-B 9 cells . Protein stability was reduced for three out of six mutations studied . Two out of three PFIC 1 mutant proteins did not interact with CDC 50 A , whereas BRIC 1 /ICP mutants displayed reduced interaction . Importantly , none of the PFIC 1 mutants were detectable in the canalicular membrane of WIF-B 9 cells , whereas all BRIC 1 /ICP mutants displayed the same cellular staining pattern as wild-type ATP 8 B 1 . Our data indicate that PFIC 1 mutations lead to the complete absence of canalicular expression , whereas in BRIC 1 /ICP residual protein is expressed in the canalicular membrane .These data provide an explanation for the difference in severity between the phenotypes of PFIC 1 and BRIC 1 .

Diseases
Validation

Diseases presenting "bric1 patients suffer from episodic periods of cholestasis that resolve spontaneously" symptom

benign recurrent intrahepatic cholestasis

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