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.
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