Alternative titles; symbols
HGNC Approved Gene Symbol: EXOSC8
Cytogenetic location: 13q13.3 Genomic coordinates (GRCh38) : 13:37,000,786-37,009,614 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q13.3 | Pontocerebellar hypoplasia, type 1C | 616081 | Autosomal recessive | 3 |
The EXOSC8 gene encodes a subunit of the exosome, a multiprotein complex that degrades or processes messenger RNA. EXOSC8 is part of the central hexamer channel of the exosome (summary by Boczonadi et al., 2014).
Neisseria gonorrhoeae opacity-associated (Opa) proteins are a family of outer membrane proteins involved in gonococcal adhesion to and invasion of human cells. Opa expression appears to be necessary for gonococcal disease. Using the yeast 2-hybrid system to screen a HeLa cell cDNA library with an N. gonorrhoeae Opa protein as bait, Williams et al. (1998) identified partial cDNAs encoding Opa-interacting protein-1 (OIP1, or TRIP6; 602933), OIP2, OIP3 (PK3; 179050), OIP4 (PRAME; 606021), and OIP5 (606020). Sequence analysis predicted that the partial OIP2 cDNA encodes a 265-amino acid peptide that is likely to be the C terminus of a longer protein. OIP2 contains a cluster of basic residues, but unlike OIP1, OIP4, and OIP5, it has no cysteine motif.
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); p10, which is homologous to the yeast Rrp40 protein (606489); 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.
Gross (2014) mapped the EXOSC8 gene to chromosome 13q13.3 based on an alignment of the EXOSC8 sequence (GenBank BC020773) 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.
Using primary human erythroblasts and mouse erythroid cells and precursors, McIver et al. (2014) found that GATA1 (305371), a master regulator of erythroid maturation, and its downstream target FOXO3 (FOXO3A; 602681) repressed expression of EXOSC8. Knockdown of Exosc8 in mouse erythroid precursors enhanced expression of a subset of Gata1-activated genes and induced premature cell cycle exit and maturation. Knockdown of Exosc9 (606180) or the exosome catalytic subunit Dis3 (607533) also induced premature erythroid cell cycle exit and maturation. McIver et al. (2014) concluded that the exosome complex inhibits erythroid cell maturation.
In affected members from 3 families, 2 of Hungarian Roma descent and 1 of Pakistani descent, with pontocerebellar hypoplasia type 1C (PCH1C; 616081), Boczonadi et al. (2014) identified 2 different homozygous missense mutations in the EXOSC8 gene (S272T, 606019.0001 and A2V, 606019.0002). The mutations were found by a combination of homozygosity mapping and exome sequencing. Patient myoblasts and EXOSC8-silenced human oligodendrocytes showed specific increases in mRNAs encoding the myelin proteins MBP (159430) and MOBP (600948), as well as an increase in SMN1 (600354) expression. Patient cells also showed reduced EXOSC3 (606489) levels. Boczonadi et al. (2014) concluded that an imbalanced supply of myelin proteins caused myelin disruption, resulting in the severe neurodegenerative phenotype.
Boczonadi et al. (2014) found that morpholino knockdown of exosc8 in zebrafish embryos resulted in abnormalities in swimming and motor escape responses and abnormal development of motor neurons in the hindbrain, as well as impaired myelination in the spinal cord. Mbp mRNA was initially increased, but later decreased, most likely due to loss of neuronal structures and the surrounding oligodendroglia. Simultaneous knockdown of zebrafish mbp and exosc8 resulted in slightly increased survival, suggesting that dysregulation of mbp expression contributes to the impaired myelination observed in exosc8-null embryos.
In 10 affected individuals from 2 unrelated consanguineous Hungarian Roma families with pontocerebellar hypoplasia type 1C (PCH1C; 616081), Boczonadi et al. (2014) identified a homozygous c.815G-C transversion in the EXOSC8 gene, resulting in a ser272-to-thr (S272T) substitution at a highly conserved residue. The mutation, which was found using a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the families. The mutation was filtered against the 1000 Genomes Project and Exome Sequencing Project databases, as well as 334 in-house control exomes. The c.815G-C mutation was found at a frequency of 3% in the general Roma population, consistent with a founder effect. Patient cells showed significantly decreased EXOSC8 protein levels.
In 2 sibs, born of consanguineous Pakistani parents, with pontocerebellar hypoplasia type 1C (PCH1C; 616081), Boczonadi et al. (2014) identified a homozygous c.5C-T transition in the EXOSC8 gene, resulting in an ala2-to-val (A2V) substitution at a highly conserved residue. The mutation, which was found using a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 138) or Exome Sequencing Project databases. Patient fibroblasts showed significantly decreased EXOSC8 protein levels.
Boczonadi, V., Muller, J. S., Pyle, A., Munkley, J., Dor, T., Quartararo, J., Ferrero, I., Karcagi, V., Giunta, M., Polvikoski, T., Birchall, D., Princzinger, A., and 15 others. EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia. Nature Commun. 5: 4287, 2014. Note: Electronic Article. [PubMed: 24989451] [Full Text: https://doi.org/10.1038/ncomms5287]
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.
McIver, S. C., Kang, Y.-A, DeVilbiss, A. W., O'Driscoll, C. A., Ouellette, J. N., Pope, N. J., Camprecios, G., Chang, C.-J., Yang, D., Bouhassira, E. E., Ghaffari, S., Bresnick, E. H. The exosome complex establishes a barricade to erythroid maturation. Blood 124: 2285-2297, 2014. [PubMed: 25115889] [Full Text: https://doi.org/10.1182/blood-2014-04-571083]
Williams, J. M., Chen, G.-C., Zhu, L., Rest, R. F. Using the yeast two-hybrid system to identify human epithelial cell proteins that bind gonococcal Opa proteins: intracellular gonococci bind pyruvate kinase via their Opa proteins and require host pyruvate for growth. Molec. Microbiol. 27: 171-186, 1998. [PubMed: 9466265] [Full Text: https://doi.org/10.1046/j.1365-2958.1998.00670.x]