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

Abstract

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.

Biallelic variants in LARS1 induce steatosis in developing zebrafish liver via enhanced autophagy

“…To obtain more efficient knock-in using genome editing, we replaced the two bases that changed the PAM sequence (Fig 3A). Among the pathogenic variants in the LARS gene (p.W201G/p.I451F) identified in our patient, we focused on the p.I451F variant, as it has been found in other Japanese patients, suggesting a Japanese founder effect, and is located within the editing domain of the LARS protein, where pathological variants have accumulated [30]. We designed a model of the larsb I451F mutation ( larsb-I451F ) to elucidate the pathogenesis of ILFS1 (Fig 3B).…”

“…An in silico analysis suggested that W201G probably damaged the protein structure and/or function (Polyphen2: score 1.000; probably damaging [http://genetics.bwh.harvard.edu/pph2/]) (S1 Table ). Another missense variant, c.1351A>T; p.I451F in exon 14 [NM_020117.9], was maternally inherited and had been previously described in a Japanese patient with ILFS1 [30]. It is located in the LARS editing domain (Fig 2A).…”

Deep phenotyping of MARS1 (interstitial lung and liver disease) and LARS1 (infantile liver failure syndrome 1) recessive multisystemic disease using Human Phenotype Ontology annotation: Overlap and differences. Case report and review of literature

“…Our review of the literature identified 14 articles, 7 on LARS1 mutations and 7 on MARS1 mutations, such that including our 3 patients, 65 patients with LARS1 or MARS1 mutations (respectively 27 and 38) have so far been described in the literature. (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) Twenty-one of these patients (32.3%) patients died: 6/27 of the patients with LARS1 mutations (4 boys and 2 girls) and 15/38 of the patients with MARS1 mutations (11 boys and 4 girls). One of the patients with a LARS1 mutation underwent liver transplantation.…”

“…Respiratory abnormalities are indeed far more frequent in patients with MARS1 mutations and precise diagnoses as alveolar proteinosis or interstitial pulmonary disease are well described. However, most recent reports of LARS1 mutations (1,8,14) also describe associated respiratory abnormalities.…”

Aminoacyl-tRNA synthetases of the multi-tRNA synthetase complex and their role in tumorigenesis

“…Multiple single amino acid changes in EPRS1, LARS1, DARS1, IARS1, and MARS1 have been reported but MSC localization and their potential roles in cancer remain to be explored [170] , [171] , [172] , [173] . Interestingly, several mutations in DARS1 (Arg460His, Pro464Leu) that cause hypomyelination with brain stem and spinal cord involvement and leg spasticity were found that might induce release from the MSC [172] .…”