From variant interpretation to structural discovery: A new Zinc-binding domain in PARS2

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• Aminoacyl-tRNA synthetases (aaRSs) are crucial enzymes for protein synthesis.
• Mitochondrial aaRSs (ARS2) have poorly characterized extra domains, complicating genetic diagnoses.
• Pathogenic variants in ARS2 genes cause diverse neurological disorders.

Purpose of the Study:

• To investigate the cause of epileptic encephalopathy in two patients with biallelic PARS2 variants.
• To characterize a novel variant in PARS2 previously predicted as "likely benign".
• To improve the understanding of ARS2 structure, function, and pathogenicity prediction.

Main Methods:

• Phenotypic evaluation of patients.
• Comparative protein-structure modeling.
• Clade-specific analysis of sequence conservation.

Main Results:

• Both patients presented with clinical features consistent with PARS2 deficiency.
• A novel PARS2 variant was identified within a previously unrecognized zinc-binding domain (ZBD).
• This ZBD is structurally similar to the ZBD in cytosolic ProRS.

Conclusions:

• The study reveals a critical ZBD in mitochondrial prolyl-tRNA synthetase (PARS2).
• Findings highlight limitations in predicting ARS2 variant pathogenicity using current tools.
• This work expands the genotypic spectrum of PARS2-related disorders and describes associated phenotypes.