Case Report: Mutation in AIMP2/P38, the Scaffold for the Multi-Trna Synthetase Complex, and Association With Progressive Neurodevelopmental Disorders

Abstract

Background: Leukodystrophies constitute a heterogeneous group of inherited disorders primarily affecting the white matter of the central nervous system. Aminoacyl-tRNA synthetases (ARSs) catalyze the attachment of an amino acids to their cognate transfer RNAs (tRNAs). Pathogenic variants in both cytosolic and mitochondrial ARSs have been linked to a broad range of neurological disorders, including hypomyelinating leukodystrophies and pontocerebellar hypoplasias (PCH). Aminoacyl tRNA synthetase-interacting multifunctional protein 2 (AIMP2), one of the three non-catalytic components of multi ARS complex, harbors anti-proliferative activity and functions as a proapoptotic factor thus promoting cell death. We report a case of a 7-month-old infant with a complex clinical presentation, including weight loss, severe anemia, skeletal abnormalities, microcephaly and MR imaging features of leukodystrophy with a novel mutation in AIMP2. Methods: Whole-exome sequencing (WES) was performed on the proband. Parental samples were analyzed by PCR amplification and Sanger sequencing. Results: Whole-exome sequencing revealed a novel variant c.A463T in the homozygous state in exon 3 (NM_001,326,607) of AIMP2 [p.(K155X)] in the proband. Parental carrier status was confirmed by target sequencing. Conclusion: Here, we present an Iranian case with leukodystrophy with a novel AIMP2 mutation. This finding broadens the mutational and phenotypic spectra of AIMP2-related leukodystrophy and offers guidance for proper genetic counselling for pre- and post-natal screenings as well as for disease management.

Keywords: AIMP2/P38; WES; leukodystrophies; multi-tRNA synthetase complex; neurodevelopmental disorders.

FIGURE 1

(A) Pedigrees of the family (B) Clinical manifestations of the proband (C) An Integrative Genomic Viewer (IGV) of homozygous nonsense variant AIMP2″ NM001326607 c.A463T, K155X (D) Position in the homozygous state in exon 3 of the variant c.A463T (NM_001,326,607) of AIMP2 [p.(K155X)]. (E) Sanger sequencing of genomic DNA confirmed the presence of a homozygous mutation in the proband and heterozygous mutation in the parents. (F) This alignment shows this position (variant) highly conserved between vertebrates.