Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype

Abstract

Brittle and ''tiger-tail'' hair is the diagnostic hallmark of trichothiodystrophy (TTD), a rare recessive disease associated with a wide spectrum of clinical features including ichthyosis, intellectual disability, decreased fertility, and short stature. As a result of premature abrogation of terminal differentiation, the hair is brittle and fragile and contains reduced cysteine content. Hypersensitivity to UV light is found in about half of individuals with TTD; all of these individuals harbor bi-allelic mutations in components of the basal transcription factor TFIIH, and these mutations lead to impaired nucleotide excision repair and basal transcription. Different genes have been found to be associated with non-photosensitive TTD (NPS-TTD); these include MPLKIP (also called TTDN1), GTF2E2 (also called TFIIEb), and RNF113A. However, a relatively large group of these individuals with NPS-TTD have remained genetically uncharacterized. Here we present the identification of an NPS-TTD-associated gene, threonyl-tRNA synthetase (TARS), found by next-generation sequencing of a group of uncharacterized individuals with NPS-TTD. One individual has compound heterozygous TARS variants, c.826A>G (p.Lys276Glu) and c.1912C>T (p.Arg638*), whereas a second individual is homozygous for the TARS variant: c.680T>C (p.Leu227Pro). We showed that these variants have a profound effect on TARS protein stability and enzymatic function. Our results expand the spectrum of genes involved in TTD to include genes implicated in amino acid charging of tRNA, which is required for the last step in gene expression, namely protein translation. We previously proposed that some of the TTD-specific features derive from subtle transcription defects as a consequence of unstable transcription factors. We now extend the definition of TTD from a transcription syndrome to a ''gene-expression'' syndrome.

Nucleolar TFIIE plays a role in ribosomal biogenesis and performance

“…We here extend this classification, and highlight a possible contribution of protein translation disturbances in the pathophysiology of TTD. Recently, mutations in aminoacyl-tRNA synthetases were identified to cause TTD (Kuo et al, 2019, Theil et al, 2019 implying that a disturbed translation process, as shown in this study, might be causal for the developmental delay and neurodegeneration observed in TTD. This assumption is based on the hypothesis that only disturbances in a common cellular signaling pathway that is affected by all genes in this genotypical heterogenous disease can explain the phenotype.…”

“…TTD is mainly attributed to a transcription syndrome (Compe, Genes et al, 2019, Theil, Mandemaker et al, 2017. However, recently discovered mutations in aminoacyl-tRNA synthetases that result in TTD may shift this classification towards a "gene expression syndrome" referred to a disturbed protein translation at the ribosome (Kuo, Theil et al, 2019, Theil, Botta et al, 2019. TFIIH mutations can also cause the premature aging disease Cockayne syndrome (CS) that resembles TTD with symptoms of developmental delay, microcephaly and neurodegeneration.…”

FARS1‐related disorders caused by bi‐allelic mutations in cytosolic phenylalanyl‐tRNA synthetase genes: Look beyond the lungs!

“…More than 60 disorders are associated with mutations in ARS genes and, depending on their individual genotype, follow both dominant or recessive inheritance patterns. [4][5][6][7][8][9][10] Cytosolic phenylalanyl-tRNA synthetase (FARS1) ranks among the most complex of the ARSs with a hetero-tetrameric structure, consisting of two FARS alpha (FARSA) and two FARS beta (FARSB) subunits. 11 The hypothesis that both genes may be associated with a similar multisystemic human disease, including features of interstitial lung disease, liver disease, neurological manifestations, and growth restriction (MIM: 619013, 613 658), needs further support.…”

In-depth analysis reveals complex molecular etiology of idiopathic cerebral palsy

“…. A very recent report introduced two individuals carrying TARS variants with trichothiodystrophy 43 , while we found a spastic hemiplagia patient (CP_014_1) with biallelic TARS variants, who presented overlapping phenotype including developmental delay, but without manifestation in hair or skin (Supplementary figure 4).…”