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. == References ==