title: A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease.
abstract: Infantile cholestatic diseases can be caused by mutations in a number of genes involved in different hepatocyte molecular pathways. Whilst some of the essential pathways have a well understood function, such as bile biosynthesis and transport, the role of the others is not known. Here we report the findings of a clinical, biochemical and molecular study of a family with three patients affected with a severe infantile cholestatic disease. A novel homozygous frameshift germline mutation (c.587delG) in the AKR1D1 gene; which encodes the enzyme Δ 4-3-oxosteroid 5β-reductase that is required for synthesis of primary bile acids and is crucial for establishment of normal bile flow, was found in all 3 patients. Although the initial bile acid analysis was inconclusive, subsequent testing confirmed the diagnosis of a bile acid biogenesis disorder. An additional novel homozygous frameshift mutation (c.3391delC) was detected in SKIV2L in one of the patients. SKIV2L encodes a homologue of a yeast ski2 protein proposed to be involved in RNA processing and mutations in SKIV2L were recently described in patients with Tricohepatoenteric syndrome (THES). A combination of autozygosity mapping and whole-exome-sequencing allowed the identification of causal mutations in this family with a complex liver phenotype. Although the initial 2 affected cousins died in the first year of life, accurate diagnosis and management of the youngest patient led to successful treatment of the liver disease and disease-free survival.
authors.affiliation: Department of Medical and Molecular Genetics and Centre for Rare Diseases and Personalised Medicine, University of Birmingham School of Medicine, Birmingham, UK. n.v.morgan@bham.ac.uk
authors.forename: Neil V
authors.initials: NV
authors.lastname: Morgan
authors.forename: Jane L
authors.initials: JL
authors.lastname: Hartley
authors.forename: Kenneth D R
authors.initials: KD
authors.lastname: Setchell
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Rachel
authors.initials: R
authors.lastname: Brown
authors.forename: Louise
authors.initials: L
authors.lastname: Tee
authors.forename: Sian
authors.initials: S
authors.lastname: Kirkham
authors.forename: Shanaz
authors.initials: S
authors.lastname: Pasha
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.forename: Deirdre A
authors.initials: DA
authors.lastname: Kelly
mesh_terms: D001647:Bile Acids and Salts / Q000378:metabolism; D002779:Cholestasis / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D003241:Consanguinity; D004265:DNA Helicases / Q000235:genetics*; D059472:Exome; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007223:Infant; D008107:Liver Diseases / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D010088:Oxidoreductases / Q000235:genetics*; D010641:Phenotype; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index
chemical_list: D001647:Bile Acids and Salts; D010088:Oxidoreductases; C021936:3-oxo-5 beta-steroid delta 4-dehydrogenase; D004265:DNA Helicases; C114718:SKIV2L protein, human