title: Bile acid-CoA ligase deficiency--a new inborn error of bile acid metabolism.
abstract: Born at 27 weeks gestation, a child of consanguineous parents of Pakistani origin required prolonged parenteral nutrition. She developed jaundice, with extensive fibrosis and architectural distortion at liver biopsy; jaundice resolved with supportive care. Serum γ-glutamyl transpeptidase values were within normal ranges. The bile acids in her plasma and urine were >85% unconjugated (non-amidated). Two genes encoding bile-acid amidation enzymes were sequenced. No mutations were found in BAAT, encoding bile acid-CoA : aminoacid N-acyl transferase. The patient was homozygous for the missense mutation c.1012C > T in SLC27A5, predicted to alter a highly conserved amino-acid residue (p.H338Y) in bile acid-CoA ligase (BACL). She also was homozygous for the missense mutation c.1772A > G in ABCB11, predicted to alter a highly conserved amino-acid residue (p.N591S) in bile salt export pump (BSEP). BACL is essential for reconjugation of bile acids deconjugated by gut bacteria, and BSEP is essential for hepatocyte-canaliculus export of conjugated bile acids. A female sibling born at term had the same bile-acid phenotype and SLC27A5 genotype, without clinical liver disease. She was heterozygous for the c.1772A > G ABCB11 mutation. This is the first report of a mutation in SLC27A5. The amidation defect may have contributed to cholestatic liver disease in the setting of prematurity, parenteral nutrition, and homozygosity for an ABCB11 mutation.
authors.affiliation: Clinical & Molecular Genetics Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Catherine P K
authors.initials: CP
authors.lastname: Chong
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
authors.forename: Patricia
authors.initials: P
authors.lastname: McClean
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.forename: Christopher
authors.initials: C
authors.lastname: Bruce
authors.forename: Jens
authors.initials: J
authors.lastname: Stahlschmidt
authors.forename: A S
authors.initials: AS
authors.lastname: Knisely
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
mesh_terms: D001647:Bile Acids and Salts / Q000737:chemistry; D002675:Child, Preschool; D003066:Coenzyme A Ligases / Q000172:deficiency* / Q000235:genetics*; D003241:Consanguinity; D017931:DNA Primers / Q000235:genetics; D004262:DNA Restriction Enzymes / Q000378:metabolism; D050612:Fatty Acid Transport Proteins / Q000235:genetics; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics*; D008957:Models, Genetic; D020125:Mutation, Missense; D010154:Pakistan; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D001647:Bile Acids and Salts; D017931:DNA Primers; D050612:Fatty Acid Transport Proteins; C484819:SLC27A5 protein, human; D004262:DNA Restriction Enzymes; D003066:Coenzyme A Ligases; C070656:bile acid-CoA ligase
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