Mutations in LARS2, Encoding Mitochondrial Leucyl-tRNA Synthetase, Lead to Premature Ovarian Failure and Hearing Loss in Perrault Syndrome

Abstract

The genetic causes of premature ovarian failure (POF) are highly heterogeneous, and causative mutations have been identified in more than ten genes so far. In two families affected by POF accompanied by hearing loss (together, these symptoms compose Perrault syndrome), exome sequencing revealed mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase: homozygous c.1565C>A (p.Thr522Asn) in a consanguineous Palestinian family and compound heterozygous c.1077delT and c.1886C>T (p.Thr629Met) in a nonconsanguineous Slovenian family. 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. A recently developed method of detecting remote homologies revealed threonine at this site in consensus sequences derived from multiple-species alignments seeded by human and E. coli residues at this region. Yeast complementation indicated that LARS2 c.1077delT is nonfunctional and that LARS2 p.Thr522Asn is partially functional. LARS2 p.Thr629Met was functional in this assay but might be insufficient as a heterozygote with the fully nonfunctional LARS2 c.1077delT allele. A known C. elegans strain with the protein-truncating alteration LARS-2 p.Trp247Ter was confirmed to be sterile. After HARS2, LARS2 is the second gene encoding mitochondrial tRNA synthetase to be found to harbor mutations leading to Perrault syndrome, further supporting a critical role for mitochondria in the maintenance of ovarian function and hearing.

LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure

“…The recombinant LARS2 p.Thr522Asn had a 9-fold loss of catalytic efficiency, consistent with yeast complementation studies that showed the yeast ortholog of LARS2 p.Thr522Asn retained partial function (Pierce et al 2013). Modeling of LARS2 on the E. coli leucyl-tRNA synthetase crystal structure indicates that Thr522 is located in the active site where the 3 0 end of the tRNA binds (Pierce et al 2013) (Fig. 2d).…”

“…LARS2 variants have previously been reported in association with sensorineural hearing loss and premature ovarian failure (Pierce et al 2013) in three siblings of Palestinian origin who were homozygous for the LARS2 p.Thr522Asn variant and a Slovenian child with compound heterozygous LARS2 p. Ile360fs*15 and p.Thr629Met variants (see Supplementary Table 3 for a comparison of phenotypes).…”

“…In some cases, overlapping clinical features have been observed from mutations in different genes. For instance, mutations in HARS2 and LARS2 are both associated with sensorineural hearing loss and progressive ovarian failure (OMIM 614926) (Pierce et al 2011;Pierce et al 2013). However, in other cases, different mutations in the same gene result in distinct phenotypes.…”

Genetics of primary ovarian insufficiency

“…The analysis of a few cohorts of 46,XX POI patients by means of high throughput techniques, such as comparative genomic hybridization array (array-CGH) and SNP array, has led to the identification of CNVs affecting several X-linked and autosomal loci with a possible role in female fertility (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Similarly, the recent application of whole-exome sequencing (WES) to a few POI multigenerational familial cases has succeeded in revealing rare single nucleotide variants affecting genes implicated in ovarian function (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). As already reported in other complex diseases characterized by a great genetic heterogeneity, it is likely that patients with POI may harbor multiple genetic variants.…”

tRN-A-RS Acts As Biomarker for Cancer and Other Diseases

“…DARS is also mutated in patients affected with leukoencephalopathy [82]. Resembling LBSL, there is another variety of leukoencephalopathy characterized by hypomyelination with brain stem and spinal cord involvement and leg spasticity, HBSL.…”