Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia

Schottmann, Gudrun; Picker-Minh, Sylvie; Schwarz, Jana Marie; Gill, Esther; Rodenburg, Richard J.; Stenzel, Werner; Kaindl, Angela M.; Schuelke, Markus

doi:10.1016/j.mito.2017.06.007

Cited by 29 publications

(31 citation statements)

References 42 publications

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“…Control muscle RNA sequences were obtained as described previously. 32 The quality of sequencing reads was checked with FastQC. Reads were aligned with the STAR (v2.5.2b) aligner and the two-pass protocol that is outlined in GATK documentation.…”

Section: Methodsmentioning

confidence: 99%

Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy

Burns

Donkervoort

Müller

et al. 2018

The American Journal of Human Genetics

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104

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The exosome is a conserved multi-protein complex that is essential for correct RNA processing. Recessive variants in exosome components EXOSC3, EXOSC8, and RBM7 cause various constellations of pontocerebellar hypoplasia (PCH), spinal muscular atrophy (SMA), and central nervous system demyelination. Here, we report on four unrelated affected individuals with recessive variants in EXOSC9 and the effect of the variants on the function of the RNA exosome in vitro in affected individuals’ fibroblasts and skeletal muscle and in vivo in zebrafish. The clinical presentation was severe, early-onset, progressive SMA-like motor neuronopathy, cerebellar atrophy, and in one affected individual, congenital fractures of the long bones. Three affected individuals of different ethnicity carried the homozygous c.41T>C (p.Leu14Pro) variant, whereas one affected individual was compound heterozygous for c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161∗). We detected reduced EXOSC9 in fibroblasts and skeletal muscle and observed a reduction of the whole multi-subunit exosome complex on blue-native polyacrylamide gel electrophoresis. RNA sequencing of fibroblasts and skeletal muscle detected significant >2-fold changes in genes involved in neuronal development and cerebellar and motor neuron degeneration, demonstrating the widespread effect of the variants. Morpholino oligonucleotide knockdown and CRISPR/Cas9-mediated mutagenesis of exosc9 in zebrafish recapitulated aspects of the human phenotype, as they have in other zebrafish models of exosomal disease. Specifically, portions of the cerebellum and hindbrain were absent, and motor neurons failed to develop and migrate properly. In summary, we show that variants in EXOSC9 result in a neurological syndrome combining cerebellar atrophy and spinal motoneuronopathy, thus expanding the list of human exosomopathies.

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Section: Methodsmentioning

confidence: 99%

Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy

Burns

Donkervoort

Müller

et al. 2018

The American Journal of Human Genetics

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104

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“…Exome sequencing of individuals with PCH1b from thirtyeight unrelated families has identified several different EXOSC3 mutations (Table 1; Fig. 2; Supplemental Table S1; Wan et al 2012;Biancheri et al 2013;Rudnik-Schöneborn et al 2013;Schwabova et al 2013;Eggens et al 2014;Di Giovambattista et al 2017;Schottmann et al 2017). In particular, 13 individuals with severe PCH1b (life span ≤2 yr) carried homozygous EXOSC3 (G31A) mutations in the N-terminal domain of EXOSC3, and 18 individuals with PCH1b that exhibited a less severe disease (life span ≥3 yr) had homozygous EXOSC3 (D132A) mutations in the S1 domain of EXOSC3.…”

Section: Wwwrnajournalorg 131mentioning

confidence: 99%

“…However, unlike EXOSC3 variants, EXOSC8 variants also cause hypomyelination in addition to PCH (Boczonadi et al 2014). Notably, like EXOSC2 variants, EXOSC8 variants impair vision and hearing, and some EXOSC3 and EXOSC8 variants confer mitochondrial defects (Boczonadi et al 2014;Di Donato et al 2016;Schottmann et al 2017).…”

Section: Comparisons and Potential Mechanisms Of Exosomelinked Diseasementioning

confidence: 99%

The RNA exosome and RNA exosome-linked disease

Morton

Kuiper

Jones

et al. 2017

RNA

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The RNA exosome is an evolutionarily conserved, ribonuclease complex that is critical for both processing and degradation of a variety of RNAs. Cofactors that associate with the RNA exosome likely dictate substrate specificity for this complex. Recently, mutations in genes encoding both structural subunits of the RNA exosome and its cofactors have been linked to human disease. Mutations in the RNA exosome genes and cause pontocerebellar hypoplasia type 1b (PCH1b) and type 1c (PCH1c), respectively, which are similar autosomal-recessive, neurodegenerative diseases. Mutations in the RNA exosome gene cause a distinct syndrome with various tissue-specific phenotypes including retinitis pigmentosa and mild intellectual disability. Mutations in genes that encode RNA exosome cofactors also cause tissue-specific diseases with complex phenotypes. How mutations in these genes give rise to distinct, tissue-specific diseases is not clear. In this review, we discuss the role of the RNA exosome complex and its cofactors in human disease, consider the amino acid changes that have been implicated in disease, and speculate on the mechanisms by which exosome gene mutations could underlie dysfunction and disease.

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“…Indeed, deleterious variants in four genes -EXOSC2, EXOSC3, EXOSC8, and EXOSC9 -encoding structural subunits of the RNA exosome and in several exosome cofactors have so far been linked to clinical phenotypes (Table 1) (18). Biallelic variants in EXOSC3, encoding a cap exosome subunit, cause pontocerebellar hypoplasia type 1b (PCH1b, OMIM 614678), a neurodegenerative condition characterized by neonatal hypotonia, feeding and swallowing difficulties, respiratory insufficiency, variable developmental delays, ataxia, lower motor neuron signs with muscle weakness and atrophy and limited survival (3,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Less common features, including seizures, nystagmus, strabismus and optic atrophy and dyskinesia, dystonia and spastic paraplegia, can be observed in patients with longer survival (24).…”

mentioning

confidence: 99%

Biallelic variants in the RNA exosome geneEXOSC5are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness

Slavotinek

Misceo

Htun

et al. 2020

Preprint

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The RNA exosome is an essential ribonuclease complex involved in the processing and degradation of both coding and noncoding RNAs. We present three patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The common clinical features of these patients comprise failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. The first patient had a deletion involving exons 5-6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His, and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess the functional consequences of pathogenic variants in EXOSC5. Loss of function for the zebrafish ortholog results in shortened and curved tails and bodies, reduced eye and head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants show defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. Overall, these findings expand the number of genes encoding RNA exosome components that have been implicated in human disease, while also suggesting that disease mechanism varies depending on the specific pathogenic variant. IntroductionThe RNA exosome is a ribonuclease complex composed of ten, evolutionarily conserved subunits that form a ring-like structure with 3'-5' exonuclease activity that is critical for the processing and degradation of a variety of RNAs both in the nucleus and cytoplasm (1-3). The exosome subunits are designated as exosome component (EXOSC) proteins in humans, mice (M. musculus) and other mammals and ribosomal RNA processing (Rrp) proteins in zebrafish (D. rerio), fruit flies (D. melanogaster) and budding yeast (S. cerevisiae), where the complex was first identified and studied (4, 5). The EXOSC4-9 subunits and their orthologs form a central, six-subunit ring that is covered by a three-subunit cap composed of EXOSC1-3. The ring-like complex creates a central channel through which RNA substrates are threaded to the catalytic subunit, DIS3 or DIS3L, at the base (6-10). In addition to DIS3 or DIS3L, the 9-subunit exosome complex also associates with another catalytic subunit, EXOSC10 at the cap. Notably, DIS3 and EXOSC10 are predominantly nuclear (7,(9)(10)(11), whereas DIS3L is mostly cytoplasmic (12).Although all six structural core ring subunits contain an RNase PH-like domain, they are all catalytically inactive due to amino acid substitutions that replace key catalytic residues (13). Thus, RNA substrates of the RNA exosome access the DIS3 catalytic subunit primarily via interactions with the non-catalytic core channel (14-16). Consistent with the critical function of the RNA exosome in the processing and decay of numerous ce...

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Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia

Cited by 29 publications

References 42 publications

Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy

Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy

The RNA exosome and RNA exosome-linked disease

Biallelic variants in the RNA exosome geneEXOSC5are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness

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