Alanine–tRNA ligase, cytoplasmic

Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth Disease type 2 (CMT2) and other peripheral neuropathies have been linked to mutations in the AARS1, GARS1, HARS1, WARS1, and YARS1 genes. Mutations in these genes can encode for faulty aminoacyl-tRNA synthetases, which affects a highly conserved amino acid in the helical domain of cytoplasmic AARS1. This disrupts the ability to charge tRNA with its corresponding amino acids, which leads to impaired protein synthesis. In AARS1, mutations are associated with both autosomal dominant and recessive forms of CMT2.

Trichothiodystrophy

In addition to its role in CMT2, mutations in the AARS1 gene have also been implicated in non-photosensitive trichothiodystrophy (NPS-TTD), a rare hereditary neurodevelopmental disorder. Trichothiodystrophy (TTD) is defined by sulfur-deficient brittle hair, nails, and scaly skin, but presents with variable clinical features. Unlike the photosensitive form of TTD (PS-TTD), which exhibits features of progressive neuropathy and accelerated aging, NPS-TTD is not associated with premature aging.

Research has identified AARS1, along with methionyl-tRNA synthetase 1 as genes in which variants can contribute to the development NPS-TTD. These variants lead to the instability of the respective enzymes which they encode, affecting the rate of tRNA charging, which is the first step in protein translation.