Characterization of mutations in ATP8B1 associated with hereditary cholestasis.

[benign recurrent intrahepatic cholestasis]

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 ATP 8 B 1 (previously FIC 1 ) may result in PFIC or BRIC . We report the genomic organization of ATP 8 B 1 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 . ATP 8 B 1 mutations were detected in 30 % and 41 %, respectively , of the PFIC and BRIC patients screened .

Diseases
Validation

Diseases presenting "specific populations" symptom

benign recurrent intrahepatic cholestasis

esophageal squamous cell carcinoma

lamellar ichthyosis

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