A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease

• Published in: Orphanet journal of rare diseases Vol. 8; no. 1; p. 74
• Main Authors: Morgan, Neil V, Hartley, Jane L, Setchell, Kenneth D R, Simpson, Michael A, Brown, Rachel, Tee, Louise, Kirkham, Sian, Pasha, Shanaz, Trembath, Richard C, Maher, Eamonn R, Gissen, Paul, Kelly, Deirdre A
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 16-05-2013; BioMed Central
• Subjects: Amino acids; Bile; Bile Acids and Salts - metabolism; Care and treatment; Cholestasis - diagnosis; Cholestasis - genetics; Cholestasis - physiopathology; Cholesterol; Colleges & universities; Consanguinity; Development and progression; DNA Helicases - genetics; Exome; Female; Frameshift Mutation; Gene mutations; Humans; Infant; Letter to the Editor; Liver; Liver diseases; Liver Diseases - diagnosis; Liver Diseases - genetics; Liver Diseases - physiopathology; Male; Medical research; Medicine, Experimental; Metabolites; Mutation; Oxidoreductases - genetics; Phenotype; Physiological aspects; Rare diseases; Rodents; Sequence Analysis, DNA; Severity of Illness Index; United States; United Kingdom
• ISSN: 1750-1172; 1750-1172
• DOI: 10.1186/1750-1172-8-74

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.