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
N1 - Publisher Copyright:
© 2019 American Society of Human Genetics
PY - 2019/8/1
Y1 - 2019/8/1
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.
KW - aminoacyl tRNA synthetase
KW - brittle hair
KW - non-photosensitive trichothiodystrophy
KW - protein translation
KW - tiger tail
KW - transcription
KW - TTD
UR - http://www.scopus.com/inward/record.url?scp=85070095744&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2019.06.017
DO - 10.1016/j.ajhg.2019.06.017
M3 - Article
C2 - 31374204
AN - SCOPUS:85070095744
SN - 0002-9297
VL - 105
SP - 434
EP - 440
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -