2. Academic Validation
  3. Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype

Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype

  • Am J Hum Genet. 2019 Aug 1;105(2):434-440. doi: 10.1016/j.ajhg.2019.06.017.
Arjan F Theil 1,  Elena Botta 2,  Anja Raams 1,  Desiree E C Smith 3,  Marisa I Mendes 3,  Giuseppina Caligiuri 2,  Sarah Giachetti 2,  Silvia Bione 2,  Roberta Carriero 2,  Giordano Liberi 2,  Luca Zardoni 2,  Sigrid M A Swagemakers 4,  Gajja S Salomons 5,  Alain Sarasin 6,  Alan Lehmann 7,  Peter J van der Spek 4,  Tomoo Ogi 8,  Jan H J Hoeijmakers 9,  Wim Vermeulen 10,  Donata Orioli 11
Affiliations

Affiliations

  • 1 Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, University Medical Center Rotterdam, 3015 GD Rotterdam, the Netherlands.
  • 2 Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, 27100 Pavia, Italy.
  • 3 Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Center and Amsterdam Gastroenterology and Metabolism, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, 1081 HZ Amsterdam, the Netherlands.
  • 4 Department of Pathology and Clinical Bioinformatics Unit, Erasmus University Medical Center, 3015 GD Rotterdam, the Netherlands.
  • 5 Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Center and Amsterdam Gastroenterology and Metabolism, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, 1081 HZ Amsterdam, the Netherlands; Genetic Metabolic Diseases, Amsterdam University Medical Center, University of Amsterdam, 1081 HZ Amsterdam, the Netherlands.
  • 6 Institut Gustave Roussy, UMR8200 CNRS, 94805 Villejuif, France.
  • 7 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.
  • 8 Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Human Genetics and Molecular Biology, Graduate School of Medicine, Nagoya University, Nagoya 464-0805, Japan.
  • 9 Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, University Medical Center Rotterdam, 3015 GD Rotterdam, the Netherlands; Princess Maxima Center for Pediatric Oncology, Oncode Institute, 3584 CS Utrecht, the Netherlands; CECAD Forschungszentrum, University of Cologne, 50931 Cologne, Germany.
  • 10 Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, University Medical Center Rotterdam, 3015 GD Rotterdam, the Netherlands. Electronic address: w.vermeulen@erasmusmc.nl.
  • 11 Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, 27100 Pavia, Italy. Electronic address: orioli@igm.cnr.it.
PMID: 31374204 DOI: 10.1016/j.ajhg.2019.06.017
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 TFIIEβ), 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.

Keywords

TTD; aminoacyl tRNA synthetase; brittle hair; non-photosensitive trichothiodystrophy; protein translation; tiger tail; transcription.

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