Universität zu Köln

Thei, Arjan F., Botta, Elena, Raams, Anja, Smith, Desiree E. C., Mendes, Marisa, I, Caligiuri, Giuseppina, Giachetti, Sarah, Bione, Silvia ORCID: 0000-0002-3924-4606, 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 ORCID: 0000-0003-3616-734X and orioli, Donata (2019). Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype. Am. J. Hum. Genet., 105 (2). S. 434 - 441. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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 YID (NPS-TTD); these include MPLKIP (also called TTDN1), GTF2E2 (also called TFIIE beta), 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 YID 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 YID from a transcription syndrome to a gene-expression syndrome.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Thei, Arjan F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Botta, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Raams, Anja UNSPECIFIED UNSPECIFIED UNSPECIFIED Smith, Desiree E. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mendes, Marisa, I UNSPECIFIED UNSPECIFIED UNSPECIFIED Caligiuri, Giuseppina UNSPECIFIED UNSPECIFIED UNSPECIFIED Giachetti, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Bione, Silvia UNSPECIFIED orcid.org/0000-0002-3924-4606 UNSPECIFIED Carriero, Roberta UNSPECIFIED UNSPECIFIED UNSPECIFIED Liberi, Giordano UNSPECIFIED UNSPECIFIED UNSPECIFIED Zardoni, Luca UNSPECIFIED UNSPECIFIED UNSPECIFIED Swagemakers, Sigrid M. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Salomons, Gajja S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sarasin, Alain UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehmann, Alan UNSPECIFIED UNSPECIFIED UNSPECIFIED van der Spek, Peter J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ogi, Tomoo UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoeijmakers, Jan H. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vermeulen, Wim UNSPECIFIED orcid.org/0000-0003-3616-734X UNSPECIFIED orioli, Donata UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-145993
DOI:	10.1016/j.ajhg.2019.06.017
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	105
Number:	2
Page Range:	S. 434 - 441
Date:	2019
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TRANSFER-RNA SYNTHETASES; DNA-REPAIR; BASAL TRANSCRIPTION; REPAIR/TRANSCRIPTION FACTOR; XERODERMA-PIGMENTOSUM; XPD MUTATIONS; FACTOR TFIIH; TTDN1 GENE; TRICHOTHIODYSTROPHY; INDIVIDUALS Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14599