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


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Authors

Morgan, Neil V 
Hartley, Jane L 
Setchell, Kenneth DR 
Simpson, Michael A 
Brown, Rachel 

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.

Description

Keywords

Bile Acids and Salts, Cholestasis, Consanguinity, DNA Helicases, Exome, Female, Frameshift Mutation, Humans, Infant, Liver Diseases, Male, Oxidoreductases, Phenotype, Sequence Analysis, DNA, Severity of Illness Index

Journal Title

Orphanet J Rare Dis

Conference Name

Journal ISSN

1750-1172
1750-1172

Volume Title

Publisher

Springer Science and Business Media LLC