LARS2

Official Full Name

leucyl-tRNA synthetase 2, mitochondrial

Organism

Homo sapiens

GeneID

23395

Background

This gene encodes a class 1 aminoacyl-tRNA synthetase, mitochondrial leucyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid. [provided by RefSeq, Jul 2008]

Synonyms

HLASA; LEURS; PRLTS4; mtLeuRS;

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Detailed Information

Recent Progress

LARS2 gene encodes a class 1 aminoacyl-tRNA synthetase, mitochondrial leucyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid. Pathogenic variants in mitochondrial aminoacyl-tRNA synthetases result in a broad range of mitochondrial respiratory chain disorders despite their shared role in mitochondrial protein synthesis. LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene. More recently, mutations in LARS2 were also found to be responsible for PRLTS (Perrault syndrome, a rare autosomal recessive disorder characterized by ovarian dysgenesis and premature ovarian failure in females, and by progressive hearing loss in both genders). Data analysis highlighted compound heterozygosity, in two patients with PRLTS, for two novel missense variations, p.Thr300Met (c.899C>T) and p.Glu638Lys (c.1912G>A) within LARS2. The segregation of the two mutations in the pedigree is compatible with the autosomal recessive inheritance of the disease. This study confirmed the role of LARS2 mutations in PRLTS pathogenesis.

More specifically speaking, some patients with Perrault syndrome exhibit neurologic features including learning disability, cerebellar ataxia, and peripheral neuropathy and are classified as type 2 while being clinically separated from those without neurological symptoms other than a hearing loss (type 1). To date, almost all reported patients with LARS2 mutations (15 patients in 8 families) have been classified as type 1. Researchers also reported female siblings with biallelic mutations in LARS2, who were classified as type 2. Thus it was concluded that Perrault syndrome patients with LARS2 mutations.

Apart from LARS2’s association with Perrault syndrome, a case containing variants in LARS2 which are concerned with a severe multisystem metabolic disorder was also revealed. The proband was born prematurely with severe lactic acidosis, hydrops, and sideroblastic anemia. She had multisystem complications with hyaline membrane disease, impaired cardiac function, a coagulopathy, pulmonary hypertension, and progressive renal disease and succumbed at 5 days of age. The discovered c.1565C>A (p.Thr522Asn) LARS2 variant has previously been associated with Perrault syndrome and both identified variants are predicted to be damaging. It was further shown that LARS2 levels were reduced in liver and complex I protein levels were reduced in patient muscle and liver. Thus it was suggested that the identified LARS2 variants are responsible for the severe multisystem clinical phenotype seen in this baby and that mutations in LARS2 can result in variable phenotypes.

To further revealed the mechanism underlying the causative role of LARS2, researchers studied two families affected by POF (primary ovary failure) accompanied by hearing loss, exome sequencing revealed mutations in LARS2. LARS2 c.1077delT leads to a frameshift at codon 360 of the 901 residue protein. LARS2 p.Thr522Asn occurs in the LARS2 catalytic domain at a site conserved from bacteria through mammals. LARS2 p.Thr629Met occurs in the LARS2 leucine-specific domain, which is adjacent to a catalytic loop critical in all species but for which primary sequence is not well conserved. Revealing the interaction site of LARS2 would help further define the role of this protein in the disease progression (Fig.1).

Fig. 1. Domain Architecture and Conservation of LARS2 and Structural Analysis of the LARS2 E. coli Ortholog. (Yang et al, 2015)

References:

Pierce, Sarah B., et al. "Mutations in LARS2, Encoding Mitochondrial Leucyl-tRNA Synthetase, Lead to Premature Ovarian Failure and Hearing Loss in Perrault Syndrome." American Journal of Human Genetics 92.4(2013):614-620.
Soldà, Giulia, et al. "First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family." Journal of Human Genetics 61.4(2016):295-300.
Riley, Lisa G., et al. "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure." Jimd Reports 28(2015):49.
Kosaki, Rika, et al. "Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with neurologic symptoms." American Journal of Medical Genetics Part A 176.2(2017).
Soldà, G, et al. "Identification by whole-exome sequencing of two novel LARS2 mutations in an Italian family with Perrault syndrome." Journal of Human Genetics 61.4(2016):295-300.

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