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

Casey, Jillian P.; McGettigan, Paul A.; Lynam‐Lennon, Niamh; McDermott, Michael; Regan, Regina; Conroy, Judith; Bourke, Billy; O'Sullivan, Jacintha; Crushell, Ellen; Lynch, Sally Ann; Ennis, Sean

doi:10.1016/j.ymgme.2012.04.017

Cited by 90 publications

(78 citation statements)

References 27 publications

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“…1A-B). Six of the nine Irish patients were reported in our original study (Casey et al 2012). Three additional Irish patients have been identified; two relatives of previously reported patients and a child from an unrelated Irish Traveller family.…”

Section: Introductionmentioning

confidence: 95%

“…Known metabolic and genetic causes of liver failure including disorders of intermediary metabolism, storage disorders, peroxisomal disorders, glycosylation disorders and mitochondrial disorders were excluded through clinical, biochemical and genetic analyses (Casey et al 2012).…”

Section: Clinical Evaluationsmentioning

confidence: 99%

“…We recently identified recessive mutations in the cytoplasmic leucyl-tRNA synthetase gene (LARS) as the cause of a multisystem disorder involving infantile liver dysfunction and acute liver failure, anemia, decompensation with minor illness, developmental delay and, in some cases, seizures and encephalopathy (Casey et al 2012). This disorder is now referred to as Infantile Liver Failure Syndrome type 1 (ILFS1 MIM #615438).…”

Section: Introductionmentioning

confidence: 99%

“…ILFS1 and ILFS2 are similar except that interstitial lung disease is additionally present in ILFS2. LARS and MARS are the first two cytoplasmic amino-acyl tRNA synthetase genes to be associated with a hepatic disorder which may suggest an overlapping disease mechanism (Casey et al 2012, van Meel et al 2013.…”

Section: Introductionmentioning

confidence: 99%

“…It is therefore plausible that proteins with the highest percentage content of leucine, which are largely immune-related proteins, will be most severely affected if LARS is not functioning efficiently (Casey et al 2012). One possible theory is that when children with LARS mutations are ill, the requirement for leucine increases due to the induction of immune-related pathways that involve proteins with high leucine content and the mutant LARS may not cope with this spike in demand.…”

Section: Introductionmentioning

confidence: 99%

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Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS

Casey

Slattery

Cotter

et al. 2015

J of Inher Metab Disea

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Summary BackgroundRecessive LARS mutations were recently reported to cause a novel syndrome, Infantile Liver Failure Syndrome Type 1 (ILFS1), in six Irish Travellers. We have since identified four additional patients, including one of Ashkenazi origin, representing the largest ILFS1 cohort to date. Our study aims to define the ILFS1 clinical phenotype to help guide diagnosis and patient management.

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Section: Introductionmentioning

confidence: 95%

Section: Clinical Evaluationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS

Casey

Slattery

Cotter

et al. 2015

J of Inher Metab Disea

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A novel multisystem disease associated with recessive mutations in the tyrosyl‐tRNA synthetase (YARS) gene

Nowaczyk

Huang

Tarnopolsky

et al. 2016

American J of Med Genetics Pt A

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Aminoacyl-tRNA synthetases (ARSs) are a group of ubiquitously expressed enzymes that are best known for their function in the first step of protein translation but have been increasingly associated with secondary functions including transcription and translation control and extracellular signaling. Mutations in numerous ARSs have been linked to a growing number of both autosomal dominant and autosomal recessive human diseases. The tyrosyl-tRNA synthetase (YARS) links the amino acid tyrosine to its cognate tRNA. We report two siblings who presented with failure to thrive (FTT), hypertriglyceridemia, developmental delay, liver dysfunction, lung cysts, and abnormal subcortical white matter. Using exome sequencing the siblings were found to harbor bi-allelic pathogenic-appearing variants within the YARS gene (NM_003680.3):c.638C>T p.(Pro213Leu) and c.1573G>A p.(Gly525Arg). These YARS variants occur in the catalytic domain and the C-terminal domain, respectively. Mutations in YARS have been previously associated with an autosomal dominant form of Charcot-Marie-Tooth (CMT); our findings suggest the disease spectrum associated with YARS dysregulation is broader than peripheral neuropathy. © 2016 Wiley Periodicals, Inc.

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Severe course with lethal hepatocellular injury and skeletal muscular dysgenesis in a neonate with infantile liver failure syndrome type 1 caused by novel LARS1 mutations

Hirata

Okamoto

Ichikawa

et al. 2020

American J of Med Genetics Pt A

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Infantile liver failure syndrome type 1 (ILFS1) is a recently recognized autosomal recessive disorder caused by deleterious mutations in the leucyl‐tRNA synthetase 1 gene (LARS1). The LARS1 enzyme is responsible for incorporation of the amino acid leucine during protein polypeptide synthesis. Individuals with LARS1 mutations typically show liver failure from infancy to early childhood during periods of illness or other physiological stress. While 25 patients from 15 families with ILFS1 have been reported in the literature, histological reports from autopsy findings are limited. We report here a premature male neonate who presented with severe intrauterine growth retardation, microcytic anemia, and fulminant liver failure, and who was a compound heterozygote for two novel deleterious mutations in LARS1. An autopsy showed fulminant hepatitis‐like hepatocellular injury and fibrogenesis in the liver and a lack of uniformity in skeletal muscle, accompanied by the disruption of striated muscle fibers. Striking dysgenesis in skeletal muscle detected in the present case indicates the effect of LARS1 functional deficiency on the musculature. Whole‐exome sequencing may be useful for neonates with unexplained early liver failure if extensive genetic and metabolic testing is inconclusive.

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

Cited by 90 publications

References 27 publications

Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS

Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS

A novel multisystem disease associated with recessive mutations in the tyrosyl‐tRNA synthetase (YARS) gene

Severe course with lethal hepatocellular injury and skeletal muscular dysgenesis in a neonate with infantile liver failure syndrome type 1 caused by novel LARS1 mutations

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