B cell dysfunction in thalamus and brainstem involvement and high lactate caused by novel mutation of EARS2 gene

TL;DR

A new mutation in the EARS2 gene causes a rare mitochondrial disease with brain and immune system issues, including B-cell dysfunction and high lactate levels.

Contribution

A novel EARS2 mutation is identified in a patient with LTBL, expanding the mutation database and linking it to B-cell dysfunction and mitochondrial issues.

Findings

A compound heterozygous EARS2 mutation (c.1304T > A and c.319 C > T) was found in a patient with LTBL.

The EARS2 mutation caused structural changes in the protein, B-cell dysfunction, and mitochondrial metabolic issues.

Decreased CD38 expression and elevated reactive oxygen species were observed in B cells.

Abstract

The EARS2 gene, a member of the mt-aaRS family, encodes mitochondrial glutamyl-tRNA synthetase (GluRS), which is involved in the synthesis of mitochondrial proteins. Pathogenic defects in EARS2 may cause mitochondrial OXPHOS deficiency, which is associated with a rare autosomal-recessive mitochondrial disease, leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL).

In this study, clinical features were obtained, and whole-exome sequencing was conducted on a patient with LTBL. B- and T-cell immunophenotyping and protein expression were analyzed using flow cytometry, and B-cell metabolism was investigated using confocal microscopy.

The patient with LTBL exhibited typical neurological manifestations, recurrent respiratory tract infections, and humoral immune disorders. Molecular analysis revealed a compound heterozygous novel mutation in c.1304T > A (p.L435Q) and a previously reported c.319 C > T (p.R107C) mutation of EARS2. The mutations led to protein structural modifications of EARS2. The patient also exhibited disrupted peripheral B-cell differentiation and B-cell receptor signal transduction. The EARS2 mutation led to decreased expression of CD38 and dysfunction of mitochondrial metabolism, with elevated reactive oxygen species levels in B cells.

We identified a novel mutation of the EARS2 gene in a patient with LTBL, expanding the mutation database. The mutation of EARS2 modified protein structure and impaired B-cell function, decreased CD38 expression, and led to dysfunction of mitochondrial metabolism, all of which may account for the recurrent respiratory tract infections and humoral immune disorders observed in LTBL.

The online version contains supplementary material available at 10.1186/s13052-025-01999-5.

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