TSEN54 mutations cause pontocerebellar hypoplasia type 5

Namavar, Yasmin; Chitayat, David; Barth, Peter; Ruissen, Fred van; Wissel, Marit B. de; Poll-Thé, Bwee Tien; Silver, Rachel; Baas, Frank

doi:10.1038/ejhg.2011.8

Cited by 46 publications

(55 citation statements)

References 11 publications

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“…Several different cellular mechanisms have been implicated including mutations in SIL1, coding for an endoplasmic reticulum resident cochaperone, which cause Marinesco-Sjogren syndrome (MSS [MIM 248800]); 1 sialic acid disorders such as Salla disease (MIM 604369); 2 disorders of peroxisome biogenesis in atypical Refsum disease (MIM 614879); 3 congenital disorders of glycosylation, especially type 1a caused by mutations in PMM2 (MIM 212065); 4 and the X-linked ID-small cerebellum syndrome caused by mutations in OPHN1 (MIM 300486), a RhoGTPase-activating protein (GAP). 5 Related phenotypes include the group designated as pontocerebellar hypoplasias, 6 11,12 and another (CHMP1A [MIM 614961]), with a dual role in protein sorting at the endosome and chromatin modification at the nucleus. 13 Other cellular processes include synaptic and cell junction function (CASK [MIM 300749]), 14 cell cycle progression, and cell division (the serine-threonine kinase VRK1 [MIM 607596]).…”

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confidence: 99%

Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome

Thomas¹,

Hj²,

Setó‐Salvia³

et al. 2014

The American Journal of Human Genetics

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Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum.

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confidence: 99%

Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome

Thomas¹,

Hj²,

Setó‐Salvia³

et al. 2014

The American Journal of Human Genetics

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“…Certain tRNA isoacceptor families are exclusively represented by intron-containing tRNAs, highlighting the importance of proper splicing. Recessive mutations in all four subunits of the tRNA splicing endonuclease complex ( TSEN ), as well as in CLP1 (cleavage and polyadenylation factor I subunit 1), a kinase involved in tRNA splicing, cause pontocerebellar hypoplasia (PCH), a heterogeneous group of neurodegenerative disorders with prenatal to neonatal onset characterized by cerebellar hypoplasia and microcephaly (Bierhals et al, 2013; Breuss et al, 2016; Karaca et al, 2014; Namavar et al, 2011; Schaffer et al, 2014). In addition, mice homozygous for a mutation in CLP1 that abolishes its kinase activity ( Clp1 K/K ) display progressive loss of spinal motor neurons, and cortical microcephaly (Hanada et al, 2013; Karaca et al, 2014).…”

Section: Defects In Trna Expression and Processing In Neurodegenerationmentioning

confidence: 99%

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

Kapur

Monaghan

Ackerman

2017

Neuron

179

167

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SUMMARY Dynamic regulation of mRNA translation initiation and elongation is essential for the survival and function of neural cells. Global reductions in translation initiation resulting from mutations in the translational machinery or inappropriate activation of the integrated stress response may contribute to pathogenesis in a subset of neurodegenerative disorders. Aberrant proteins generated by non-canonical translation initiation may be a factor in the neuron death observed in the nucleotide repeat expansion diseases. Dysfunction of central components of the elongation machinery, such as the tRNAs and their associated enzymes, can cause translation infidelity and ribosome stalling, resulting in neurodegeneration. Taken together, dysregulation of mRNA translation is emerging as a unifying mechanism underlying the pathogenesis of many neurodegenerative disorders.

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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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TSEN54 mutations cause pontocerebellar hypoplasia type 5

Cited by 46 publications

References 11 publications

Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome

Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

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

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