AIMP2 – Hypomyelinating Leukodystrophy 17

Hypomyelinating Leukodystrophy 17 is an autosomal recessive white matter disorder caused by biallelic loss-of-function mutations in the aminoacyl-tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) gene. Computational analysis of 343 nonsynonymous SNVs in AIMP2 revealed that 18 variants map to conserved functional domains and 10 reduce protein stability, including the recurrent c.382C>T (p.Pro128Ser) substitution, suggesting deleterious effects on protein structure and function (PMID:39640834).

Cellular studies of a disease-associated nonsense allele, p.Tyr35Ter, demonstrate that mutant AIMP2 aggregates in the Golgi of oligodendroglial FBD-102b cells, triggers CASP2-dependent Golgi stress signaling, and abolishes morphological differentiation, whereas CASP2 knockdown restores process formation and web-like structures characteristic of mature oligodendrocytes (PMID:34523057). These findings provide mechanistic insight into how AIMP2 loss-of-function impairs myelination.

References

• Heliyon • 2024 • An extensive in silico analysis of missense mutations of the human AIMP2 gene. PMID:39640834
• Neurochemical research • 2022 • Knockdown of Golgi Stress-Responsive Caspase-2 Ameliorates HLD17-Associated AIMP2 Mutant-Mediated Inhibition of Oligodendroglial Cell Morphological Differentiation. PMID:34523057

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