Novel alanyl-tRNA synthetase 2 (AARS2) homozygous mutation in a consanguineous Chinese family with premature ovarian insufficiency

Objective: To explore the candidate pathogenic gene in a premature ovarian insufficiency (POI) proband from a consanguineous marriage and detect the potential effects of mutation on cellular energy metabolism.

Design: Genetic and functional studies.

Setting: Reproductive medicine center.

Patient(s): A patient with POI, from a consanguineous family, and her family members were recruited from the Reproductive Center of the First Affiliated Hospital of Anhui Medical University.

Intervention(s): Whole exome sequencing (WES) was performed for the proband. Variation revealed by WES sequencing was validated by Sanger sequencing in her family. Sequencing data were combined with those of other sporadic cases listed in public databases to identify the causative gene.

Main outcome measure(s): Rare homozygous nonsynonymous variants were identified and included in subsequent analysis. Metabolic analyzes were performed using Seahorse XFe96 analyzers to measure oxygen consumption and then obtain further results of ATP production and extracellular acidification rate. The differences in energy metabolism measurements between wild type and mutation were analyzed and compared.

Result(s): A novel alanyl-tRNA synthetase 2 (AARS2) homozygous mutation (NM_020745: exon2: c.337G>C: p. G113R) was identified in the aminoacylation region using WES. The mutation was highly conserved among species and predicted to be disease causing. AARS2 encodes mitochondrial alanyl-tRNA synthetase, which attaches alanine onto tRNA-ala. AARS2 mutations were previously reported in female leukodystrophy patients with POI. In mitochondrial stress tests, the ATP productions of the mutation group (3.58 ± 0.46 fmol/min/cell) was significantly lower than that of the wild type group (6.96 ± 1.56 fmol/min/cell).

Conclusion(s): This is the first report of a homozygous pathogenic AARS2 mutation in POI. This mutation may lead to incorrect aminoacylation of tRNA, affect mitochondrial translation, and cause oxidative phosphorylation defects, which may be responsible for POI.