A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease
Morgan, Neil V
Hartley, Jane L
Setchell, Kenneth DR
Simpson, Michael A
Trembath, Richard C
Kelly, Deirdre A
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Morgan, N. V., Hartley, J. L., Setchell, K. D., Simpson, M. A., Brown, R., Tee, L., Kirkham, S., et al. (2013). A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease. https://doi.org/10.1186/1750-1172-8-74
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.
External DOI: https://doi.org/10.1186/1750-1172-8-74
This record's URL: http://www.dspace.cam.ac.uk/handle/1810/244597
Rights Holder: Neil V Morgan et al.; licensee BioMed Central Ltd.