Universität zu Köln

Botta, Elena, Theil, Arjan F., Raams, Anja, Caligiuri, Giuseppina, Giachetti, Sarah, Bione, Silvia, Accadia, Maria, Lombardi, Anita, Smith, Desiree E. C., Mendes, Marisa, I, Swagemakers, Sigrid M. A., Van der Spek, Peter J., Salomons, Gajja S., Hoeijmakers, Jan H. J., Yesodharan, Dhanya, Nampoothiri, Sheela ORCID: 0000-0002-9575-0722, Ogi, Tomoo, Lehmann, Alan R., Orioli, Donata and Vermeulen, Wim ORCID: 0000-0003-3616-734X (2021). Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy. Hum. Mol. Genet., 30 (18). S. 1711 - 1721. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

Trichothiodystrophy (TTD) is a rare hereditary neurodevelopmental disorder defined by sulfur-deficient brittle hair and nails and scaly skin, but with otherwise remarkably variable clinical features. The photosensitive TTD (PS-TTD) forms exhibits in addition to progressive neuropathy and other features of segmental accelerated aging and is associated with impaired genome maintenance and transcription. New factors involved in various steps of gene expression have been identified for the different non-photosensitive forms of TTD (NPS-TTD), which do not appear to show features of premature aging. Here, we identify alanyl-tRNA synthetase 1 and methionyl-tRNA synthetase 1 variants as new gene defects that cause NPS-TTD. These variants result in the instability of the respective gene products alanyl- and methionyl-tRNA synthetase. These findings extend our previous observations that TTD mutations affect the stability of the corresponding proteins and emphasize this phenomenon as a common feature of TTD. Functional studies in skin fibroblasts from affected individuals demonstrate that these new variants also impact on the rate of tRNA charging, which is the first step in protein translation. The extension of reduced abundance of TTD factors to translation as well as transcription redefines TTD as a syndrome in which proteins involved in gene expression are unstable.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Botta, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Theil, Arjan F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Raams, Anja UNSPECIFIED UNSPECIFIED UNSPECIFIED Caligiuri, Giuseppina UNSPECIFIED UNSPECIFIED UNSPECIFIED Giachetti, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Bione, Silvia UNSPECIFIED UNSPECIFIED UNSPECIFIED Accadia, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Lombardi, Anita UNSPECIFIED UNSPECIFIED UNSPECIFIED Smith, Desiree E. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mendes, Marisa, I UNSPECIFIED UNSPECIFIED UNSPECIFIED Swagemakers, Sigrid M. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Van der Spek, Peter J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Salomons, Gajja S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoeijmakers, Jan H. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yesodharan, Dhanya UNSPECIFIED UNSPECIFIED UNSPECIFIED Nampoothiri, Sheela UNSPECIFIED orcid.org/0000-0002-9575-0722 UNSPECIFIED Ogi, Tomoo UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehmann, Alan R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Orioli, Donata UNSPECIFIED UNSPECIFIED UNSPECIFIED Vermeulen, Wim UNSPECIFIED orcid.org/0000-0003-3616-734X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-600199
DOI:	10.1093/hmg/ddab123
Journal or Publication Title:	Hum. Mol. Genet.
Volume:	30
Number:	18
Page Range:	S. 1711 - 1721
Date:	2021
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2083
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TRANSFER-RNA SYNTHETASE; NUCLEOTIDE EXCISION-REPAIR; DNA-REPAIR; BASAL TRANSCRIPTION; TFIIH; HETEROGENEITY; DEFICIENT; DISORDER Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/60019