Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype

Arjan F. Theil, Elena Botta, Anja Raams, Desiree E. C. Smith, Marisa I. Mendes, Giuseppina Caligiuri, Sarah Giachetti, Silvia Bione, Roberta Carriero, Giordano Liberi, Luca Zardoni, Sigrid M. A. Swagemakers, Gajja S. Salomons, Alain Sarasin, Alan Lehmann, Peter J. van der Spek, Tomoo Ogi, Jan H. J. Hoeijmakers, Wim Vermeulen, Donata Orioli

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)434-440
JournalAmerican journal of human genetics
Volume105
Issue number2
DOIs
Publication statusPublished - 2019

Cite this

Theil, Arjan F. ; Botta, Elena ; Raams, Anja ; Smith, Desiree E. C. ; Mendes, Marisa I. ; Caligiuri, Giuseppina ; Giachetti, Sarah ; Bione, Silvia ; Carriero, Roberta ; Liberi, Giordano ; Zardoni, Luca ; Swagemakers, Sigrid M. A. ; Salomons, Gajja S. ; Sarasin, Alain ; Lehmann, Alan ; van der Spek, Peter J. ; Ogi, Tomoo ; Hoeijmakers, Jan H. J. ; Vermeulen, Wim ; Orioli, Donata. / Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype. In: American journal of human genetics. 2019 ; Vol. 105, No. 2. pp. 434-440.
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title = "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 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.",
author = "Theil, {Arjan F.} and Elena Botta and Anja Raams and Smith, {Desiree E. C.} and Mendes, {Marisa I.} and Giuseppina Caligiuri and Sarah Giachetti and Silvia Bione and Roberta Carriero and Giordano Liberi and Luca Zardoni and Swagemakers, {Sigrid M. A.} and Salomons, {Gajja S.} and Alain Sarasin and Alan Lehmann and {van der Spek}, {Peter J.} and Tomoo Ogi and Hoeijmakers, {Jan H. J.} and Wim Vermeulen and Donata Orioli",
year = "2019",
doi = "10.1016/j.ajhg.2019.06.017",
language = "English",
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pages = "434--440",
journal = "American journal of human genetics",
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Theil, AF, Botta, E, Raams, A, Smith, DEC, Mendes, MI, Caligiuri, G, Giachetti, S, Bione, S, Carriero, R, Liberi, G, Zardoni, L, Swagemakers, SMA, Salomons, GS, Sarasin, A, Lehmann, A, van der Spek, PJ, Ogi, T, Hoeijmakers, JHJ, Vermeulen, W & Orioli, D 2019, 'Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype' American journal of human genetics, vol. 105, no. 2, pp. 434-440. https://doi.org/10.1016/j.ajhg.2019.06.017

Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype. / Theil, Arjan F.; Botta, Elena; Raams, Anja; Smith, Desiree E. C.; Mendes, Marisa I.; Caligiuri, Giuseppina; Giachetti, Sarah; Bione, Silvia; Carriero, Roberta; Liberi, Giordano; Zardoni, Luca; Swagemakers, Sigrid M. A.; Salomons, Gajja S.; Sarasin, Alain; Lehmann, Alan; van der Spek, Peter J.; Ogi, Tomoo; Hoeijmakers, Jan H. J.; Vermeulen, Wim; Orioli, Donata.

In: American journal of human genetics, Vol. 105, No. 2, 2019, p. 434-440.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype

AU - Theil, Arjan F.

AU - Botta, Elena

AU - Raams, Anja

AU - Smith, Desiree E. C.

AU - Mendes, Marisa I.

AU - Caligiuri, Giuseppina

AU - Giachetti, Sarah

AU - Bione, Silvia

AU - Carriero, Roberta

AU - Liberi, Giordano

AU - Zardoni, Luca

AU - Swagemakers, Sigrid M. A.

AU - Salomons, Gajja S.

AU - Sarasin, Alain

AU - Lehmann, Alan

AU - van der Spek, Peter J.

AU - Ogi, Tomoo

AU - Hoeijmakers, Jan H. J.

AU - Vermeulen, Wim

AU - Orioli, Donata

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/31374204

U2 - 10.1016/j.ajhg.2019.06.017

DO - 10.1016/j.ajhg.2019.06.017

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JO - American journal of human genetics

JF - American journal of human genetics

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