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Keywords = translational infidelity

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21 pages, 3375 KiB  
Article
Ribosomal Dysfunction Is a Common Pathomechanism in Different Forms of Trichothiodystrophy
by Gaojie Zhu, Fatima Khalid, Danhui Zhang, Zhouli Cao, Pallab Maity, Hans A. Kestler, Donata Orioli, Karin Scharffetter-Kochanek and Sebastian Iben
Cells 2023, 12(14), 1877; https://doi.org/10.3390/cells12141877 - 17 Jul 2023
Cited by 4 | Viewed by 2123
Abstract
Mutations in a broad variety of genes can provoke the severe childhood disorder trichothiodystrophy (TTD) that is classified as a DNA repair disease or a transcription syndrome of RNA polymerase II. In an attempt to identify the common underlying pathomechanism of TTD we [...] Read more.
Mutations in a broad variety of genes can provoke the severe childhood disorder trichothiodystrophy (TTD) that is classified as a DNA repair disease or a transcription syndrome of RNA polymerase II. In an attempt to identify the common underlying pathomechanism of TTD we performed a knockout/knockdown of the two unrelated TTD factors TTDN1 and RNF113A and investigated the consequences on ribosomal biogenesis and performance. Interestingly, interference with these TTD factors created a nearly uniform impact on RNA polymerase I transcription with downregulation of UBF, disturbed rRNA processing and reduction of the backbone of the small ribosomal subunit rRNA 18S. This was accompanied by a reduced quality of decoding in protein translation and the accumulation of misfolded and carbonylated proteins, indicating a loss of protein homeostasis (proteostasis). As the loss of proteostasis by the ribosome has been identified in the other forms of TTD, here we postulate that ribosomal dysfunction is a common underlying pathomechanism of TTD. Full article
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15 pages, 1786 KiB  
Review
Molecular Strategies for RPGR Gene Therapy
by Jasmina Cehajic Kapetanovic, Michelle E McClements, Cristina Martinez-Fernandez de la Camara and Robert E MacLaren
Genes 2019, 10(9), 674; https://doi.org/10.3390/genes10090674 - 4 Sep 2019
Cited by 36 | Viewed by 7471
Abstract
Mutations affecting the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the commonest cause of X-linked and recessive retinitis pigmentosa (RP), accounting for 10%–20% of all cases of RP. The phenotype is one of the most severe amongst all causes of RP, [...] Read more.
Mutations affecting the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the commonest cause of X-linked and recessive retinitis pigmentosa (RP), accounting for 10%–20% of all cases of RP. The phenotype is one of the most severe amongst all causes of RP, characteristic for its early onset and rapid progression to blindness in young people. At present there is no cure for RPGR-related retinal disease. Recently, however, there have been important advances in RPGR research from bench to bedside that increased our understanding of RPGR function and led to the development of potential therapies, including the progress of adeno-associated viral (AAV)-mediated gene replacement therapy into clinical trials. This manuscript discusses the advances in molecular research, which have connected the RPGR protein with an important post-translational modification, known as glutamylation, that is essential for its optimal function as a key regulator of photoreceptor ciliary transport. In addition, we review key pre-clinical research that addressed challenges encountered during development of therapeutic vectors caused by high infidelity of the RPGR genomic sequence. Finally, we discuss the structure of three current phase I/II clinical trials based on three AAV vectors and RPGR sequences and link the rationale behind the use of the different vectors back to the bench research that led to their development. Full article
(This article belongs to the Special Issue Molecular Therapies for Inherited Retinal Diseases)
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