Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype

Area of Science:

• Genetics
• Molecular Biology
• Rare Diseases

Background:

• Trichothiodystrophy (TTD) is a rare genetic disorder characterized by brittle hair and diverse clinical manifestations.
• Some TTD cases involve mutations in transcription factor TFIIH, leading to UV sensitivity and impaired DNA repair.
• Genetic causes for non-photosensitive TTD (NPS-TTD) remain unidentified in a significant patient group.

Purpose of the Study:

• To identify novel genetic causes of non-photosensitive TTD (NPS-TTD) in previously uncharacterized individuals.
• To expand the understanding of TTD pathogenesis beyond transcription defects.

Main Methods:

• Next-generation sequencing was employed to analyze the genomes of individuals with uncharacterized NPS-TTD.
• Functional analysis was performed to assess the impact of identified variants on TARS protein stability and enzymatic activity.

Main Results:

• The study identified mutations in the threonyl-tRNA synthetase (TARS) gene as a cause of NPS-TTD.
• Identified TARS variants (compound heterozygous and homozygous) significantly impaired protein stability and function.
• This finding links TTD to defects in amino acid charging of tRNA, essential for protein translation.

Conclusions:

• The TARS gene is implicated in NPS-TTD, broadening the genetic spectrum of the disease.
• TTD can result from defects in gene expression beyond transcription, encompassing translation.
• This research redefines TTD as a "gene-expression" syndrome, not solely a transcription syndrome.