Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy

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.

C. elegansTFIIH subunit GTF-2H5/TTDA is a non-essential transcription factor indispensable for DNA repair

“…In recent years, besides mutations in XPB, XPD and TTDA, multiple additional mutations in genes have been identified to cause TTD or TTD-like syndromes, among which are mutations in transcription initiation factor TFIIE, which all affect the stability of proteins involved in different steps of transcription and translation (Kuschal et al , 2016; Theil et al , 2017; Botta et al , 2021; Kuo et al , 2019; Theil et al , 2019; Tessarech et al , 2020; Corbett et al , 2015). Together, these have put forward the unifying idea that TTD is caused by instability of proteins involved in gene expression.…”

Trichothiodystrophy hair shafts display distinct ultrastructural features

“…A genetic basis for TTD has now been established. Causative mutations have been reported in 10 genes: DNA repair/transcription genes XPB, XPD and TTDA 2,12 ; a M-phase-specific MLK1 interacting protein TTDN1 whose function is not clear [13][14][15] ; GTF2E2 which has a role in the initiation of RNA transcription 16,17 ; CARS1, TARS1, AARS1, MARS1, whose function is to load each amino acid onto its specific cognate tRNA through aminoacylation reactions 18 ; and RNF113A which has a role in the transcriptional process. 19,20 Since the original work characterizing the ultrastructure of TTD hair preceded the genetic findings, we have examined sections of TTD hair with known defects in the XPD gene (ERCC2) by transmission electron microscopy to find whether they differ from previous findings and from each other.…”

Response to Leidi et al

“…These individuals share clinical and pathological features of a nonphotosensitive form of trichothiodystrophy (sulfur-deficient brittle hair and nails and ichthyosis), similar to those seen in other cytosolic aminoacylation disorders (deficiencies of CARS1, MARS1, and TARS1), likely further expanding the phenotypic spectrum of AARS1 deficency. 4 Second, this case also underscores the difficulty in interpreting variants in single individuals, even in cases where functional data may be available. As stated by the authors, the decrease in AARS1 activity is milder in this individual than in other published cases with AARS1 variants.…”

“…For example, we had referred to the case report of Marten et al 3 of an affected patient with bi-allelic AARS1 variants and decreased enzymatic activity that showed early infantile onset with microcephaly, white matter signal hyperintensities, and developmental delay with improvement over time and, in addition, recurrent liver failure triggered by febrile illness, as seen in other cytosolic aminoacylation disorders (deficiencies of FARS1, IARS1, LARS1, MARS1, QARS1, and YARS1). In the meantime, Botta et al 4 have reported two patients with bi-allelic AARS1 variants and decreased enzymatic activity, the first showing microcephaly, developmental delay, and delayed myelination with periventricular diffusion restriction on brain magnetic resonance imaging and the second showing developmental delay and neurologic regression. These individuals share clinical and pathological features of a nonphotosensitive form of trichothiodystrophy (sulfur-deficient brittle hair and nails and ichthyosis), similar to those seen in other cytosolic aminoacylation disorders (deficiencies of CARS1, MARS1, and TARS1), likely further expanding the phenotypic spectrum of AARS1 deficency.…”

“…As stated by the authors, the decrease in AARS1 activity is milder in this individual than in other published cases with AARS1 variants. [2][3][4] No normative data exist on this enzyme activity, as might be available in more common disorders. In particular, no data exist on the range of enzyme activities that might be expected in heterozygous subjects or if an individual carries one pathogenic variant but a second variant of uncertain significance.…”