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 "wide range" symptom

22q11.2 deletion syndrome

acute rheumatic fever

adrenomyeloneuropathy

alexander disease

allergic bronchopulmonary aspergillosis

alpha-thalassemia

aromatase deficiency

benign recurrent intrahepatic cholestasis

cadasil

carcinoma of the gallbladder

congenital toxoplasmosis

cowden syndrome

cystinuria

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

fabry disease

gm1 gangliosidosis

harlequin ichthyosis

homocystinuria without methylmalonic aciduria

hydrocephalus with stenosis of the aqueduct of sylvius

legionellosis

neonatal adrenoleukodystrophy

oral submucous fibrosis

pendred syndrome

phenylketonuria

pleomorphic liposarcoma

primary effusion lymphoma

primary hyperoxaluria type 1

proteus syndrome

pyruvate dehydrogenase deficiency

scrub typhus

systemic capillary leak syndrome

thoracic outlet syndrome

triple a syndrome

trochlear dysplasia

well-differentiated liposarcoma

werner syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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