Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy

Elena Botta, Arjan F. Theil, Anja Raams, Giuseppina Caligiuri, Sarah Giachetti, Silvia Bione, Maria Accadia, Anita Lombardi, Desiree E.C. Smith, Marisa I. Mendes, Sigrid M.A. Swagemakers, Peter J. Van Der Spek, Gajja S. Salomons, Jan H.J. Hoeijmakers, Dhanya Yesodharan, Sheela Nampoothiri, Tomoo Ogi, Alan R. Lehmann, Donata Orioli*, Wim Vermeulen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

20 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1711-1720
Number of pages10
JournalHuman Molecular Genetics
Issue number18
Early online date28 Apr 2021
Publication statusPublished - 15 Sept 2021

Bibliographical note

Funding Information:
The work was supported by Associazione Italiana Ricerca sul Cancro (Id. 21737) toD.O.; Telethon Foundation (GEP13022) to E.B.; European Research Council Advanced grant (233424), Oncode Institute (partly financed by the Dutch Cancer Society),NIH grant (PO1 AG017242),Memorabel and Chembridge (ZonMW) and BBoL (NWO-ENW), EJP-RD project TC-NER RD20-113 and the Deutsche Forschungsgemeinschaft (SFB 829) to J.H.J.H.; European Research Council Advanced grant (340988), Dutch Science Organization (NWO) ZonMW division (912.12.132) and Oncode Institute (partly financed by the Dutch Cancer Society) to W.V.; Bioinformatrics support was partially supported by various H2020 Bigmedilytics, Moodstratification, ImmuneAID and TranSYS grants to P.J.v.d.S.

Publisher Copyright:
© The Author(s) 2021.


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