Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy

Hum Mol Genet. 2021 Aug 28;30(18):1711-1720. doi: 10.1093/hmg/ddab123.

Elena Botta ¹, Arjan F Theil ², Anja Raams ², Giuseppina Caligiuri ¹, Sarah Giachetti ¹, Silvia Bione ¹, Maria Accadia ³, Anita Lombardi ¹, Desiree E C Smith ⁴, Marisa I Mendes ⁴, Sigrid M A Swagemakers ⁵, Peter J van der Spek ⁵, Gajja S Salomons ⁴ ⁶, Jan H J Hoeijmakers ² ⁷ ⁸, Dhanya Yesodharan ⁹, Sheela Nampoothiri ⁹, Tomoo Ogi ¹⁰ ¹¹, Alan R Lehmann ¹², Donata Orioli ¹, Wim Vermeulen ²

Affiliations

1 Istituto di Genetica Molecolare 'Luigi Luca Cavalli-Sforza' (IGM) CNR, Via Abbiategrasso 207, Pavia 27100, Italy.
2 Department of Molecular Genetics, Oncode Institute, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, Rotterdam 3015 GD, The Netherlands.
3 Medical Genetics Service, Hospital 'Cardinale G. Panico', Via San Pio X Tricase 73039, Italy.
4 Metabolic Unit, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology & Metabolism, Amsterdam 1081 HZ, The Netherlands.
5 Department of Pathology, Clinical Bioinformatics Unit, Erasmus University Medical Center Rotterdam, Dr. Molewaterplein 40, Rotterdam 3015 GD, The Netherlands.
6 Laboratory of Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 AZ, The Netherlands.
7 Oncode Institute, Princess Maxima Center for Pediatric Oncology, Utrecht 3584 CS, The Netherlands.
8 Institute for Genome Stability in Ageing and Disease, CECAD Forschungszentrum, University of Cologne, Cologne 50931, Germany.
9 Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, AIMS Ponekkara PO, Cochin 682041, Kerala, India.
10 Department of Genetics, Research Institute of Environmental Medicine (RIEM), Nagoya University, Nagoya 464-8601, Japan.
11 Department of Human Genetics and Molecular Biology, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan.
12 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Famer, Brighton BN1 9RQ, UK.

PMID: 33909043 DOI: 10.1093/hmg/ddab123

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.

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