Alternative titles; symbols
HGNC Approved Gene Symbol: EXOSC2
Cytogenetic location: 9q34.12 Genomic coordinates (GRCh38) : 9:130,693,760-130,704,894 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.12 | Short stature, hearing loss, retinitis pigmentosa, and distinctive facies | 617763 | Autosomal recessive | 3 |
The EXOCS2 gene encodes ribosomal RNA-processing protein-4 (RRP4), a core component of the RNA exosome. The RNA exosome is a multiprotein complex that plays key roles in RNA processing and degradation (summary by Di Donato et al., 2016).
Mitchell et al. (1997) cloned the human homolog of the yeast gene rrp4p (Mitchell et al., 1996). The protein encoded by this gene is required for a 3-prime to 5-prime exonuclease activity that generates the 3-prime end of the 5.8S rRNA. The yeast protein, as well as its human homolog, is only 1 enzymatic subunit of a multienzyme ribonuclease complex that Mitchell et al. (1997) referred to as the 'exosome.' The human protein is 43% identical to the yeast protein. Expression of the human RRP4 gene in yeast complemented the mutation in the rrp4.1 strain.
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; 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 (606493). They also identified 2 exosome-associated factors, p1 (600478) and p14 (MPP6; 605500), that were not homologous to any yeast exosome components.
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.
Gross (2014) mapped the EXOSC2 gene to chromosome 9q34.12 based on an alignment of the EXOSC2 sequence (GenBank BC000747) with the genomic sequence (GRCh37).
EXOSC2 Mutations in Short Stature, Hearing Loss, Retinitis Pigmentosa, and Distinctive Facies
In 3 patients from 2 unrelated German families with short stature, hearing loss, retinitis pigmentosa, and distinctive facies (SHRF; 617763), Di Donato et al. (2016) identified homozygous or compound heterozygous mutations in the EXOSC2 gene (G30V, 602238.0001 and G198D, 602238.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in both families. The G30V variant was found in all 3 patients and at a low frequency in German controls, suggesting a common founder allele in this population. Functional studies of the variants and studies of patient cells were not performed, but structural modeling suggested that the variants were deleterious.
Functional Studies of EXOSC2 Mutations
By Western blot and immunoprecipitation analyses, Yang et al. (2020) showed that the G198D mutation, but not the G30V mutation, decreased EXOSC2 protein stability and impaired its interactions with other RNA exosome components. Morevoer, the G198V mutant protein was nonfunctional and was associated with compromised cell proliferation, as expression of the G198V mutant did not rescue decreased cell proliferation in EXOSC2-deficient keratinocytes. RNA-sequencing analysis identified several deregulated RNAs in SHRF patient B-lymphoblasts and EXOSC2-knockout primary cultured keratinocytes, indicating that EXOSC2 regulates RNA metabolism. In vivo study with a Drosophila model demonstrated that rrp4, the functional homolog of EXOSC2 in fly, was an essential gene and critical for eye development and maintenance, muscle ultrastructure, wing vein development, and autophagy. Subsequent in vitro analysis revealed an autophagy defect in EXOSC2-deficient human cells.
In 2 patients from the same German family (family 1) with short stature, hearing loss, retinitis pigmentosa, and distinctive facies (SHRF; 617763), Di Donato et al. (2016) identified a homozygous c.89G-T transversion (c.89G-T, NM_014285.5) in exon 1 of the EXOSC2 gene, resulting in a gly30-to-val (G30V) substitution at a conserved residue in the NT domain. The G30V substitution was predicted to disrupt EXOSC2 protein interaction with EXOSC4 (606491). An unrelated patient from another German family (family 2) with a similar disorder was compound heterozygous for G30V and a c.593G-A transition in exon 7, resulting in a gly198-to-asp (G198D; 602238.0002) substitution at a conserved residue in the KH domain. The G198D variant was predicted to alter the beta-hairpin structure of the protein and possibly interfere with RNA recruiting and binding. The mutations, which were found by whole-exome sequencing, segregated with the disorder in both families. The G30V variant was found in heterozygous state in 1 of 1,000 local German control individuals (frequency of 0.0005) and at a low frequency in the ExAC database (0.00002), whereas G198D was not found in the German controls. Neither variant was found in the 1000 Genomes Project database. Functional studies of the variants and studies of patient cells were not performed.
By Western blot and immunoprecipitation analyses, Yang et al. (2020) showed that the G198D mutation, but not the G30V mutation, decreased EXOSC2 protein stability and impaired its interactions with other RNA exosome components. Moreover, the G198V mutant protein was nonfunctional and was associated with compromised cell proliferation, as expression of the G198V mutant did not rescue decreased cell proliferation in EXOSC2-deficient keratinocytes. RNA-sequencing analysis identified several deregulated RNAs in SHRF patient B-lymphoblasts and EXOSC2-knockout primary cultured keratinocytes, indicating that EXOSC2 regulates RNA metabolism. Subsequent in vitro analysis revealed an autophagy defect in EXOSC2-deficient human cells.
For discussion of the c.593G-A transition (c.593G-A, NM_014285.5) in exon 7 of the EXOSC2 gene, resulting in a gly198-to-asp (G198D) substitution, that was found in compound heterozygous state in a patient with short stature, hearing loss, retinitis pigmentosa, and distinctive facies (SHRF; 617763) by Di Donato et al. (2016), see 602238.0001.
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]
Di Donato, N., Neuhann, T., Kahlert, A.-K., Klink, B., Hackmann, K., Neuhann, I., Novotna, B., Schallner, J., Krause, C., Glass, I. A., Parnell, S. E., Genet-Pages, A., and 9 others. Mutations in EXOSC2 are associated with a novel syndrome characterised by retinitis pigmentosa, progressive hearing loss, premature ageing, short stature, mild intellectual disability and distinctive gestalt. J. Med. Genet. 53: 419-425, 2016. [PubMed: 26843489] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103511]
Gross, M. B. Personal Communication. Baltimore, Md. 6/25/2014.
Mitchell, P., Petfalski, E., Shevchenko, A., Mann, M., Tollervey, D. The exosome: a conserved eukaryotic RNA processing complex containing multiple 3-prime to 5-prime exoribonucleases. Cell 91: 457-466, 1997. [PubMed: 9390555] [Full Text: https://doi.org/10.1016/s0092-8674(00)80432-8]
Mitchell, P., Petfalski, E., Tollervey, D. The 3-prime end of yeast 5.8S rRNA is generated by an exonuclease processing mechanism. Genes Dev. 10: 502-513, 1996. [PubMed: 8600032] [Full Text: https://doi.org/10.1101/gad.10.4.502]
Yang, X., Bayat, V., DiDonato, N., Zhao, Y., Zarnegar, B., Siprashvili, Z., Lopez-Pajares, V., Sun, T., Tao, S., Li, C., Rump, A., Khavari, P., Lu, B. Genetic and genomic studies of pathogenic EXOSC2 mutations in the newly described disease SHRF implicate the autophagy pathway in disease pathogenesis. Hum. Molec. Genet. 29: 541-553, 2020. [PubMed: 31628467] [Full Text: https://doi.org/10.1093/hmg/ddz251]