Identification of a mutation in LARS as a novel cause of infantile hepatopathy

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Title: Identification of a mutation in LARS as a novel cause of infantile hepatopathy
Authors: Casey, Jillian
McGettigan, Paul A.
Lynam-Lennon, Niamh
Regan, Regina
Conroy, Judith
Bourke, Billy
Lynch, Sally
Ennis, Sean
et al.
Permanent link: http://hdl.handle.net/10197/5794
Date: Jul-2012
Abstract: Infantile hepatopathies are life-threatening liver disorders that manifest in the first few months of life. We report on a consanguineous Irish Traveller family that includes six individuals presenting with acute liver failure in the first few months of life. Additional symptoms include anaemia, renal tubulopathy, developmental delay, seizures, failure to thrive and deterioration of liver function with minor illness. The multisystem manifestations suggested a possible mitochondrial basis to the disorder. However, known causes of childhood liver failure and mitochondrial disease were excluded in this family by biochemical, metabolic and genetic analyses. We aimed to identify the underlying risk gene using homozygosity mapping and whole exome sequencing. SNP homozygosity mapping identified a candidate locus at 5q31.3–q33.1. Whole exome sequencing identified 1 novel homozygous missense mutation within the 5q31.3–q33.1 candidate region that segregated with the hepatopathy. The candidate mutation is located in the LARS gene which encodes a cytoplasmic leucyl-tRNA synthetase enzyme responsible for exclusively attaching leucine to its cognate tRNA during protein translation. Knock-down of LARS in HEK293 cells did not impact on mitochondrial function even when the cells were put under physiological stress. The molecular studies confirm the findings of the patients' biochemical and genetic analyses which show that the hepatopathy is not a mitochondrial-based dysfunction problem, despite clinical appearances. This study highlights the clinical utility of homozygosity mapping and exome sequencing in diagnosing recessive liver disorders. It reports mutation of a cytoplasmic aminoacyl-tRNA synthetase enzyme as a possible novel cause of infantile hepatopathy and underscores the need to consider mutations in LARS in patients with liver disease and multisystem presentations.
Funding Details: Health Research Board
Irish Research Council for Science, Engineering and Technology
Science Foundation Ireland
Type of material: Journal Article
Publisher: Elsevier
Journal: Molecular Genetics and Metabolism
Volume: 106
Issue: 3
Start page: 351
End page: 358
Copyright (published version): 2012 Elsevier
Keywords: Infantile hepatopathyMultisystem presentationIrish TravellerLARSAminoacyl-tRNA synthetaseMitochondrial
DOI: 10.1016/j.ymgme.2012.04.017
Language: en
Status of Item: Peer reviewed
Appears in Collections:Biomolecular and Biomedical Science Research Collection

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