tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia

Budde, Birgit; Namavar, Yasmin; Barth, Peter; Poll-Thé, Bwee Tien; Nürnberg, Gudrun; Becker, Christian; Ruissen, Fred van; Weterman, Marian A. J.; Fluiter, Kees; Beek, Erik T. Te; Aronica, Eleonora; Knaap, Marjo S. van der; Höhne, Wolfgang; Toliat, Mohammad Reza; Crow, Yanick J.; Steinlin, Maja; Voït, Thomas; Roelens, Filip; Brussel, Wim; Brockmann, Knut; Kyllerman, Mårten; Boltshauser, Eugen; Hammersen, G.; Willemsen, M.A.A.P.; Basel‐Vanagaite, Lina; Krägeloh‐Mann, Ingeborg; Vries, Linda S. de; Sztriha, László; Muntoni, Francesco; Ferrie, Colin D.; Battini, Roberta; Hennekam, Raoul C. M.; Grillo, Eugênio; Beemer, Frits A.; Stoets, Loes M E; Wollnik, Bernd; Nürnberg, Peter; Baas, Frank

doi:10.1038/ng.204

Cited by 228 publications

(248 citation statements)

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“…Homozygosity for the p.A307S TSEN54 mutation results in PCH2. 3 The c.468+2T4C is located in the donor splice site of intron 5, which makes skipping of exon 5 likely. This was confirmed with Alamut software, this tool uses four different splice site prediction algorithms (http://www.interactive-biosoftware.com/ alamut.html).…”

Section: Resultsmentioning

confidence: 99%

“…In most cases an alanine to serine substitution (p.A307S) in TSEN54 is found, whereas rare cases show mutations in TSEN2 and TSEN34. 1,3,5 PCH4 presents a more severe form of PCH including hypertonia and severe clonus and usually more pronounced cerebellar hypoplasia (see Table 1). Nine cases of genetically confirmed PCH4 have been described so far, of which eight were compound heterozygote for a nonsense mutation or a splice site mutation and the common p.A307S missense mutation in the TSEN54 gene.…”

Section: Introductionmentioning

confidence: 99%

“…1 Mutations in different genes have been identified in four of them: PCH1, PCH2, PCH4 and PCH6. [1][2][3][4] PCH2 is the most common subtype and is characterized by jitteriness and the development of dyskinesia and choreatic movements. Other criteria include swallowing problems, central visual failure and the absence of primary optic atrophy.…”

Section: Introductionmentioning

confidence: 99%

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TSEN54 mutations cause pontocerebellar hypoplasia type 5

et al. 2011

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Pontocerebellar hypoplasia (PCH) is a group of autosomal recessive neurodegenerative disorders characterized by prenatal onset of stunted brain growth and progressive atrophy predominantly affecting cerebellum, pons and olivary nuclei, and to a lesser extent also the cerebral cortex. Six subtypes (PCH1-6) were described and genes for four types (PCH1, 2, 4 and 6) were identified. Mutations in the tRNA splicing endonuclease subunit (TSEN) genes 54, 2 and 34 are found in PCH2 and PCH4. One family with severe prenatal onset of PCH has been the only representative of PCH5 published so far, and the molecular genetic status of PCH5 has not been ascertained until now. We screened the previously reported PCH5 family for mutations in the TSEN54 gene. The PCH5 patient was found to be the result of compound heterozygosity for the common TSEN54 mutation (p.A307S) plus a novel splice site mutation. The mutations associated with PCH5 are similar to what has been reported in PCH4. Thus, PCH5, PCH4 and PCH2 represent a spectrum of clinical manifestations caused by different mutations in the TSEN genes. We, therefore, propose to classify PCH2, PCH4 and PCH5 as TSEN mutation spectrum disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TSEN54 mutations cause pontocerebellar hypoplasia type 5

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“…Newly discovered pathways that generate tRNA fragments document roles of the fragments in translation regulation and cellular responses to stress (Yamasaki et al 2009;reviewed in Parker 2012). Due to all these functions, alterations in the rate of tRNA transcription or defects in various of the post-transcriptional processing steps results in numerous human diseases including neuronal disorders (reviewed in Lemmens et al 2010) and pontocerebellar hypoplasia (Budde et al 2008). Despite the importance and medical implications, much remains to be learned about tRNA biosynthesis, turnover, and subcellular dynamics.…”

Section: Contents Continuedmentioning

confidence: 99%

Transfer RNA Post-Transcriptional Processing, Turnover, and Subcellular Dynamics in the YeastSaccharomyces cerevisiae

2013

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Transfer RNAs (tRNAs) are essential for protein synthesis. In eukaryotes, tRNA biosynthesis employs a specialized RNA polymerase that generates initial transcripts that must be subsequently altered via a multitude of post-transcriptional steps before the tRNAs beome mature molecules that function in protein synthesis. Genetic, genomic, biochemical, and cell biological approaches possible in the powerful Saccharomyces cerevisiae system have led to exciting advances in our understandings of tRNA post-transcriptional processing as well as to novel insights into tRNA turnover and tRNA subcellular dynamics. tRNA processing steps include removal of transcribed leader and trailer sequences, addition of CCA to the 39 mature sequence and, for tRNA His , addition of a 59 G. About 20% of yeast tRNAs are encoded by intron-containing genes. The three-step splicing process to remove the introns surprisingly occurs in the cytoplasm in yeast and each of the splicing enzymes appears to moonlight in functions in addition to tRNA splicing. There are 25 different nucleoside modifications that are added post-transcriptionally, creating tRNAs in which 15% of the residues are nucleosides other than A, G, U, or C. These modified nucleosides serve numerous important functions including tRNA discrimination, translation fidelity, and tRNA quality control. Mature tRNAs are very stable, but nevertheless yeast cells possess multiple pathways to degrade inappropriately processed or folded tRNAs. Mature tRNAs are also dynamic in cells, moving from the cytoplasm to the nucleus and back again to the cytoplasm; the mechanism and function of this retrograde process is poorly understood. Here, the state of knowledge for tRNA post-transcriptional processing, turnover, and subcellular dynamics is addressed, highlighting the questions that remain. TABLE OF CONTENTS Abstract 43Introduction 44

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“…Like PCH1b, PCH1c is caused by mutations in a gene encoding an RNA exosome core subunit, EXOSC8 (Boczonadi et al 2014) ( Figure 1A). However, most PCH subtypes are caused by mutations in genes encoding tRNA splicing endonuclease subunits that function in tRNA processing (PCH2a,2b,2c,4,5,and 10) (Budde et al 2008;Namavar et al 2011;Hanada et al 2013;Schaffer et al 2014), a selenocysteinyl tRNA charging enzyme (PCH2d) (Agamy et al 2010) or a mitochondrial arginyl-tRNA synthetase (PCH6) (Edvardson et al 2007). A few PCH subtypes are caused by mutations that have no apparent link to the RNA exosome or tRNA, such as in genes encoding vaccinia-related kinase (PCH1a) (Renbaum et al 2009), chromatin modifying protein 1A (PCH8) (Akizu et al 2013), and adenosine monophosphate deaminase 2 (PCH9) (Mochida et al 2012).…”

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Insight into the RNA Exosome Complex Through Modeling Pontocerebellar Hypoplasia Type 1b Disease Mutations in Yeast

et al. 2017

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Pontocerebellar hypoplasia type 1b (PCH1b) is an autosomal recessive disorder that causes cerebellar hypoplasia and spinal motor neuron degeneration, leading to mortality in early childhood. PCH1b is caused by mutations in the RNA exosome subunit gene, EXOSC3. The RNA exosome is an evolutionarily conserved complex, consisting of nine different core subunits, and one or two 39-59 exoribonuclease subunits, that mediates several RNA degradation and processing steps. The goal of this study is to assess the functional consequences of the amino acid substitutions that have been identified in EXOSC3 in PCH1b patients. To analyze these EXOSC3 substitutions, we generated the corresponding amino acid substitutions in the Saccharomyces cerevisiae ortholog of EXOSC3, Rrp40. We find that the rrp40 variants corresponding to EXOSC3-G31A and -D132A do not affect yeast function when expressed as the sole copy of the essential Rrp40 protein. In contrast, the rrp40-W195R variant, corresponding to EXOSC3-W238R in PCH1b patients, impacts cell growth and RNA exosome function when expressed as the sole copy of Rrp40. The rrp40-W195R protein is unstable, and does not associate efficiently with the RNA exosome in cells that also express wild-type Rrp40. Consistent with these findings in yeast, the levels of mouse EXOSC3 variants are reduced compared to wild-type EXOSC3 in a neuronal cell line. These data suggest that cells possess a mechanism for optimal assembly of functional RNA exosome complex that can discriminate between wildtype and variant exosome subunits. Budding yeast can therefore serve as a useful tool to understand the molecular defects in the RNA exosome caused by PCH1b-associated amino acid substitutions in EXOSC3, and potentially extending to disease-associated substitutions in other exosome subunits.KEYWORDS pontocerebellar hypoplasia type 1b; RNA exosome; EXOSC3; Rrp40; EXOSC2; RNA processing/degradation T HE RNA exosome is an evolutionarily conserved ribonuclease complex that is responsible for several essential RNA processing and degradation steps (Mitchell et al. 1997;Allmang et al. 1999;Schneider and Tollervey 2013). Major exosome substrates include mRNA, rRNA, and small RNAs. In addition to degrading aberrant and unneeded transcripts, the RNA exosome also trims precursor RNAs, including 5.8S rRNA (Mitchell et al. 1996). The RNA exosome thus plays critical roles in both RNA degradation and maturation.The subunits of the RNA exosome complex are evolutionarily conserved and many were first identified in Saccharomyces cerevisiae in a screen for ribosomal RNA processing (rrp) mutants (Mitchell et al. 1996(Mitchell et al. , 1997Allmang et al. 1999). S. cerevisiae Rrp subunits correspond to human EXOSC subunits. The functions of the RNA exosome have been extensively characterized in budding yeast (Sloan et al. 2012), and many are conserved in humans (Schilders et al. 2005;Staals et al. 2010;Lubas et al. 2011Lubas et al. , 2015 the RNA exosome, six subunits comprise a core ring, and three putative RNA-binding sub...

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tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia

Cited by 228 publications

References 18 publications

TSEN54 mutations cause pontocerebellar hypoplasia type 5

TSEN54 mutations cause pontocerebellar hypoplasia type 5

Transfer RNA Post-Transcriptional Processing, Turnover, and Subcellular Dynamics in the YeastSaccharomyces cerevisiae

Insight into the RNA Exosome Complex Through Modeling Pontocerebellar Hypoplasia Type 1b Disease Mutations in Yeast

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