Alternative titles; symbols
HGNC Approved Gene Symbol: EXOSC3
Cytogenetic location: 9p13.2 Genomic coordinates (GRCh38): 9:37,779,714-37,785,092 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p13.2 | Pontocerebellar hypoplasia, type 1B | 614678 | Autosomal recessive | 3 |
The EXOSC3 gene encodes a core component of the human RNA exosome complex that is present in the cytoplasm and the nucleus and especially enriched in the nucleolus (Brouwer et al., 2001).
Inherently unstable mammalian mRNAs contain AU-rich elements (AREs) within their 3-prime untranslated regions. In yeast, 3-prime-to-5-prime mRNA degradation is mediated by the exosome, a multisubunit particle. Chen et al. (2001) purified and characterized the human exosome by mass spectrometry and found its composition to be similar to its yeast counterpart. They identified the following protein subunits within the human exosome: p7, which is homologous to the yeast Rrp4 protein (602238); p8, which is homologous to the yeast Rrp42 protein (606488); p9, which is homologous to the yeast Rrp43 protein (OIP2; 606019); p10, which is homologous to the yeast Rrp40 protein; p11, which is homologous to the yeast Mtr3 protein (606490); p12A, which is homologous to the yeast Rrp41 protein (606491); p12B, which is homologous to the yeast Rrp46 protein (606492); and p13, which is homologous to the yeast Csl4 protein (606493). They also identified 2 exosome-associated factors, p1 (600478) and p14 (MPP6; 605500), that were not homologous to any yeast exosome components.
By searching an EST database for homologs of yeast exosome components, followed by PCR on a teratocarcinoma cell line and 5-prime RACE using placenta RNA, Brouwer et al. (2001) isolated cDNAs encoding RRP40, RRP41, and RRP46. The deduced 275-amino acid RRP40 protein is 88% and 30% identical to the mouse and yeast sequences, respectively. Western blot analysis and immunofluorescence microscopy showed expression of a 31-kD protein in the nucleus, with additional forms expressed in the cytoplasm and the highest concentration in nucleolus.
There are multiple alternatively spliced forms of EXOSC3, with the longest reading frame encoding a 275-residue protein (summary by Wan et al., 2012).
Wan et al. (2012) stated that the EXOSC3 gene contains 4 exons.
Gross (2014) mapped the EXOSC3 gene to chromosome 9p13.2 based on an alignment of the EXOSC3 sequence (GenBank AF281132) with the genomic sequence (GRCh37).
Using a cell-free RNA decay system, Chen et al. (2001) demonstrated that the mammalian exosome is required for rapid degradation of ARE-containing RNAs but not for poly(A) shortening. They found that the mammalian exosome does not recognize ARE-containing RNAs on its own. ARE recognition required certain ARE-binding proteins that could interact with the exosome and recruit it to unstable RNAs, thereby promoting their rapid degradation.
Functional analysis by Brouwer et al. (2001) supported the conclusion that RRP40 is present in human exosomes in a complex displaying 3-prime-to-5-prime exonuclease activity.
In affected members of 9 families with autosomal recessive pontocerebellar hypoplasia type 1B (PCH1B; 614678), Wan et al. (2012) identified homozygous or compound heterozygous mutations in the EXOSC3 gene (see, e.g., 606489.0001-606489.0005). The first mutation was identified by genomewide scan and exome sequencing of a family with 4 affected brothers. The phenotype was severe and characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. There was diffuse muscle weakness, progressive microcephaly, global and developmental delay, and brainstem involvement. The findings indicated that proper RNA processing is important for the development and survival of cerebellar and spinal motor neurons.
Wan et al. (2012) found that morpholino knockdown of Exosc3 in zebrafish embryos caused embryonic maldevelopment, with small brain size, particularly in the hindbrain, a short and curved spine, and poor motility. There was diminished expression of dorsal hindbrain progenitor-specific markers and cerebellar-specific markers compared to controls. The defects were largely rescued by coinjection with wildtype zebrafish Exosc3 mRNA.
Pefanis et al. (2014) generated a mouse model in which the essential subunit Exosc3 was conditionally deleted in B cells. These Exosc3-deficient B cells lacked the ability to undergo normal levels of class switch recombination and somatic hypermutation, 2 mutagenic DNA processes used to generate antibody diversity via the B-cell mutator protein AID (605257). The transcriptome of Exosc3-deficient B cells revealed the presence of many novel RNA exosome substrate noncoding RNAs (ncRNAs). RNA exosome substrate RNAs include xTSS-RNAs, transcription start site (TSS)-associated antisense transcripts that can exceed 500 basepairs in length and are transcribed divergently from cognate coding gene transcripts. xTSS-RNAs are most strongly expressed at genes that accumulate AID-mediated somatic mutations and/or are frequent translocation partners of DNA double-strand breaks generated at the IgG heavy chain locus (Igh; 147100) in B cells. Strikingly, translocations near TSSs or within gene bodies occur over regions of RNA exosome substrate ncRNA expression. These RNA exosome-regulated, antisense-transcribed regions of the B-cell genome recruit AID and accumulate single-strand DNA structures containing RNA-DNA hybrids. Pefanis et al. (2014) proposed that RNA exosome regulation of ncRNA recruits AID to single-strand DNA-forming sites of antisense and divergent transcription in the B-cell genome, thereby creating a link between ncRNA transcription and overall maintenance of B-cell genomic integrity.
In 4 brothers from a family of American and European ancestry with pontocerebellar hypoplasia type 1B (PCH1B; 614678), Wan et al. (2012) identified a homozygous 395A-C transversion in exon 2 of the EXOSC3 gene, resulting in an asp132-to-ala (D132A) substitution in a highly conserved residue in the putative RNA-binding S1 domain, which may be important for intersubunit interaction within the exosome complex. The mutation was identified by genomewide scan and exome sequencing, and confirmed by Sanger sequencing. Sequencing of this gene identified the same homozygous mutation in affected individuals from 3 additional families with the disorder; 2 of these families were consanguineous. Haplotype analysis of 3 of the families with a homozygous D132A mutation was consistent with a remote common ancestor. Affected individuals in 3 additional families carried the D132A mutation in compound heterozygosity with another pathogenic mutation in the EXOSC3 gene (see, e.g., 606489.0002 and 606489.0003). All available parents were unaffected and heterozygous for 1 of the mutations, which were not found in 379 control individuals. The phenotype consisted of neonatal onset of severe hypotonia, often with respiratory insufficiency, and global developmental delay, without achieving any motor milestones or speech, and progressive microcephaly. Other features included oculomotor apraxia, progressive muscle wasting, and distal contractures. Brain MRI showed marked cerebellar and pontine atrophy. Postmortem examination showed severe loss of cerebellar and spinal motor neurons.
In 2 teenaged sibs of Bangladeshi descent with PCH1B, Zanni et al. (2013) identified compound heterozygous mutations in the EXOSC3 gene: D132A, and a c.238G-T transversion, resulting in a val80-to-phe (V80F; 606489.0006) substitution at a conserved residue in the N-terminal domain. The mutations were found by exome sequencing and filtered against the dbSNP (build 135) and 1000 Genomes Project databases; D132A was observed in 6 of 4,870 control exomes (allele frequency of 0.0012). The unaffected parents and 2 unaffected sibs were heterozygous for 1 of the mutations. Functional studies of the variants were not performed. The patients had a relatively mild form of the disorder, with delayed motor development, onset of spasticity in childhood, and mild to moderate intellectual disability, but without hypotonia or microcephaly. The report expanded the phenotypic spectrum associated with EXOSC3 mutations to include hereditary spastic paraplegia.
In an 11-month-old Australian boy with pontocerebellar hypoplasia type 1B (PCH1B; 614678), Wan et al. (2012) identified compound heterozygosity for 2 mutations in the EXOSC3 gene: a 415G-C transversion in exon 2 resulting in an ala139-to-pro (A139P) substitution at a highly conserved residue in the RNA-binding S1 domain, and D132A (606489.0001). Neither mutation was found in 379 control individuals.
In a boy from New Caledonia with pontocerebellar hypoplasia type 1B (PCH1B; 614678), Wan et al. (2012) identified compound heterozygosity for 2 mutations in the EXOSC3 gene: a 10-bp deletion (294_303del) in exon 1, predicted to result in premature termination (99fsTer11) or nonsense-mediated mRNA decay, and D132A (606489.0001). Neither mutation was found in 379 control individuals.
In 2 Czech sibs with pontocerebellar hypoplasia type 1B (PCH1B; 614678), Wan et al. (2012) identified compound heterozygosity for 2 mutations in the EXOSC3 gene: a 92G-C transversion in exon 1, resulting in a gly31-to-ala (G31A) substitution at a highly conserved residue in the N-terminal domain, and a 712T-C transition in exon 4, resulting in a trp238-to-arg (W238R; 606489.0005) substitution at a highly conserved residue in the putative RNA-binding KH domain. Another unrelated Czech boy with the disorder was homozygous for the G31A mutation. Neither mutation was found in 379 control individuals.
Schwabova et al. (2013) identified a homozygous G31A mutation in 2 unrelated Czech children of Roma descent with PCH1B. The heterozygous mutation was found in 4 (4.4%) of 90 unrelated Roma control individuals, and haplotype analysis suggested a founder effect. The patients had a severe form of the disorder, with death in the first year of life.
For discussion of the trp238-to-arg (W238R) mutation in the EXOSC3 gene that was found in compound heterozygous state in 2 patients with pontocerebellar hypoplasia type 1B (PCH1B; 614678) by Wan et al. (2012), see 606489.0004.
For discussion of the val80-to-phe (V80F) mutation in the EXOSC3 gene that was found in compound heterozygous state in 2 patients with pontocerebellar hypoplasia type 1B (PCH1B; 614678) by Zanni et al. (2013), see 606489.0001.
In 2 pairs of sibs from a large consanguineous family of Arab origin with a mild form of pontocerebellar hypoplasia type 1B (PCH1B; 614678) presenting as complicated hereditary spastic paraplegia with variable cognitive impairment, Halevy et al. (2014) identified a homozygous c.571G-T transversion in the EXOSC3 gene, resulting in a gly191-to-cys (G191C) substitution at a conserved residue in the S1-like domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in both families. It was not present in the dbSNP (build 129) or 1000 Genomes Project databases. Functional studies of the variant were not performed. The patients were 12 to 21 years of age at the time of the report. All patients had mild cerebellar signs, including nystagmus with or without intention tremor and dysmetria, and brain imaging of all patients showed mild hypoplasia and atrophy of the lower part of the vermis with a normal pons. None had microcephaly or lower motor neuron signs, and spinal imaging was normal. Halevy et al. (2014) emphasized the mild phenotype in these patients.
Brouwer, R., Allmang, C., Raijmakers, R., van Aarssen, Y., Egberts, W. V., Petfalski, E., van Venrooij, W. J., Tollervey, D., Pruijn, G. J. M. Three novel components of the human exosome. J. Biol. Chem. 276: 6177-6184, 2001. [PubMed: 11110791] [Full Text: https://doi.org/10.1074/jbc.M007603200]
Chen, C.-Y., Gherzi, R., Ong, S.-E., Chan, E. L., Raijmakers, R., Pruijn, G. J. M., Stoecklin, G., Moroni, C., Mann, M., Karin, M. AU binding proteins recruit the exosome to degrade ARE-containing mRNAs. Cell 107: 451-464, 2001. [PubMed: 11719186] [Full Text: https://doi.org/10.1016/s0092-8674(01)00578-5]
Gross, M. B. Personal Communication. Baltimore, Md. 6/25/2014.
Halevy, A., Lerer, I., Cohen, R., Kornreich, L., Shuper, A., Gamliel, M., Zimerman, B.-E., Korabi, I., Meiner, V., Straussberg, R., Lossos, A. Novel EXOSC3 mutation causes complicated hereditary spastic paraplegia. J. Neurol. 261: 2165-2169, 2014. [PubMed: 25149867] [Full Text: https://doi.org/10.1007/s00415-014-7457-x]
Pefanis, E., Wang, J., Rothschild, G., Lim, J., Chao, J., Rabadan, R., Economides, A. N., Basu, U. Noncoding RNA transcription targets AID to divergently transcribed loci in B cells. Nature 514: 389-393, 2014. [PubMed: 25119026] [Full Text: https://doi.org/10.1038/nature13580]
Schwabova, J., Brozkova, D. S., Petrak, B., Mojzisova, M., Pavlickova, K., Haberlova, J., Mrazkova, L., Hedvicakova, P., Hornofova, L., Kaluzova, M., Fencl, F., Krutova, M., Zamecnik, J., Seeman, P. Homozygous EXOSC3 mutation c.92G-C, p.G31A is a founder mutation causing severe pontocerebellar hypoplasia type 1 among the Czech Roma. J. Neurogenet. 27: 163-169, 2013. [PubMed: 23883322] [Full Text: https://doi.org/10.3109/01677063.2013.814651]
Wan, J., Yourshaw, M., Mamsa, H., Rudnik-Schoneborn, S., Menezes, M. P., Hong, J. E., Leong, D. W., Senderek, J., Salman, M. S., Chitayat, D., Seeman, P., von Moers, A., and 14 others. Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. Nature Genet. 44: 704-708, 2012. [PubMed: 22544365] [Full Text: https://doi.org/10.1038/ng.2254]
Zanni, G., Scotton, C., Passarelli, C., Fang, M., Barresi, S., Dallapiccola, B., Wu, B., Gualandi, F., Ferlini, A., Bertini, E., Wei, W. Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3. Neurogenetics 14: 247-250, 2013. [PubMed: 23975261] [Full Text: https://doi.org/10.1007/s10048-013-0371-z]