Alternative titles; symbols
HGNC Approved Gene Symbol: EXOSC1
Cytogenetic location: 10q24.1 Genomic coordinates (GRCh38) : 10:97,435,909-97,446,006 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.1 | ?Pontocerebellar hypoplasia, type 1F | 619304 | Autosomal recessive | 3 |
The EXOSC1 gene encodes a structural component of the RNA exosome complex that is involved in the general processing and degradation of coding and noncoding RNAs (summary by Somashekar et al., 2021).
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 (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. They also identified 2 exosome-associated factors, p1 (600478) and p14 (MPP6; 605500), that were not homologous to any yeast exosome components.
Raijmakers et al. (2002) stated that the CSL4 protein contains 195 amino acids and has a molecular mass of 21 kD.
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 mammalian 2-hybrid and GST pull-down analyses, Raijmakers et al. (2002) found that the CSL4 protein, but not mutant forms lacking N- or C-terminal residues, interacted directly with RRP42 and RRP46. The deletion mutants were also unable to interact with the exosome. RRP42 and RRP46 did not interact with each other.
Gross (2014) mapped the EXOSC1 gene to chromosome 10q24.1 based on an alignment of the EXOSC1 sequence (GenBank BC022067) with the genomic sequence (GRCh37).
In an 8-month-old boy, born of consanguineous Indian parents, with pontocerebellar hypoplasia type 1F (PCH1F; 619304), Somashekar et al. (2021) identified a homozygous missense mutation in the EXOSC1 gene (S35L; 606493.0001). The mutation, which was found by exome sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Patient fibroblasts showed a significant reduction in the EXOSC1 protein compared to controls, and further studies showed decreased levels of the overall exosome complex. Additional functional studies of the variant were not performed.
In an 8-month-old boy, born of consanguineous Indian parents, with pontocerebellar hypoplasia, type 1F (PCH1F; 619304), Somashekar et al. (2021) identified a homozygous c.104C-T transition (c.104C-T, NM_016046.5) in EXOSC1 gene, resulting in a ser35-to-leu (S35L) substitution at a conserved residue in the N-terminal domain. The mutation, which was found by exome sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Patient fibroblasts showed a significant reduction in the EXOSC1 protein compared to controls, and further studies showed decreased levels of the overall exosome complex. Additional functional studies of the variant were not performed.
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.
Raijmakers, R., Noordman, Y. E., van Venrooij, W. J., Pruijn, G. J. M. Protein-protein interactions of hCsl4p with other human exosome subunits. J. Molec. Biol. 315: 809-818, 2002. [PubMed: 11812149] [Full Text: https://doi.org/10.1006/jmbi.2001.5265]
Somashekar, P. H., Kaur, P., Stephen, J., Guleria, V. S., Kadavigere, R., Girisha, K. M., Bielas, S., Upadhyai, P., Shukla, A. Bi-allelic missense variant, p.Ser35Leu in EXOSC1 is associated with pontocerebellar hypoplasia. Clin. Genet. 99: 594-600, 2021. [PubMed: 33463720] [Full Text: https://doi.org/10.1111/cge.13928]