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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.

SUBMITTER: Botta E

PROVIDER: S-EPMC8411986 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy.

Botta Elena E Theil Arjan F AF Raams Anja A Caligiuri Giuseppina G Caligiuri Giuseppina G Giachetti Sarah S Bione Silvia S Accadia Maria M Lombardi Anita A Smith Desiree E C DEC Mendes Marisa I MI Swagemakers Sigrid M A SMA van der Spek Peter J PJ Salomons Gajja S GS Hoeijmakers Jan H J JHJ Yesodharan Dhanya D Nampoothiri Sheela S Ogi Tomoo T Lehmann Alan R AR Orioli Donata D Vermeulen Wim W

Human molecular genetics 20210801 18

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 ...[more]

PMID: 33909043

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Project description:ObjectiveTrichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and multisystem abnormalities. Many TTD patients have a defect in known DNA repair genes. This report systematically evaluates the ocular manifestations of the largest-to-date cohort of TTD patients and xeroderma pigmentosum (XP)/TTD patients.DesignCase series.ParticipantsThirty-two participants, ages 1 to 30 years, referred to the National Eye Institute for examination from 2001 to 2010; 25 had TTD and 7 had XP/TTD.MethodsComplete, age- and developmental stage-appropriate ophthalmic examination.Main outcome measuresVisual acuity (VA), best-corrected VA, ocular motility, state of the ocular surface and corneal endothelial cell density, corneal diameter, and lens assessment.ResultsDevelopmental abnormalities included microcornea (44% TTD), microphthalmia (8% TTD, 14% XP/TTD), nystagmus (40% TTD), and infantile cataracts (56% TTD, 86% XP/TTD). Corrective lenses were required by 65% of the participants, and decreased best-corrected VA was present in 28% of TTD patients and 71% of XP/TTD patients. Degenerative changes included dry eye (32% TTD, 57% XP/TTD) and ocular surface disease identified by ocular surface staining with fluorescein (32% TTD) that usually are exhibited by much older patients in the general population. The 2 oldest TTD patients exhibited clinical signs of retinal/macular degeneration. Four XP/TTD patients presented with corneal neovascularization.ConclusionsThese TTD and XP/TTD study participants had a wide variety of ocular findings including refractive error, infantile cataracts, microcornea, nystagmus, and dry eye/ocular surface disease. Although many of these can be ascribed to abnormal development--likely owing to abnormalities in basal transcription of critical genes--patients may also have a degenerative course.Financial disclosure(s)Proprietary or commercial disclosures may be found after the references.

Dataset Information

Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy.

Publications

Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy.

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