Alternative titles; symbols
HGNC Approved Gene Symbol: EXOSC5
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38) : 19:41,386,374-41,397,359 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | Cerebellar ataxia, brain abnormalities, and cardiac conduction defects | 619576 | Autosomal recessive | 3 |
The EXOSC5 gene encodes a structural subunit of the ring-like component of the RNA exosome, which is critical for the processing and degradation of a variety of RNAs in both the nucleus and cytoplasm (summary by Slavotinek et al., 2020).
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; 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 235-amino acid RRP46 protein is 89% and approximately 28% identical to the mouse and yeast sequences, respectively. Western blot analysis and immunofluorescence microscopy showed expression of a 26-kD protein in the nucleus, with additional forms expressed in the cytoplasm and the highest concentration in nucleolus.
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 RRP41 is present in human exosomes in a complex displaying 3-prime-to-5-prime exonuclease activity.
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 EXOSC5 gene to chromosome 19q13.2 based on an alignment of the EXOSC5 sequence (GenBank AF281134) with the genomic sequence (GRCh37).
In 3 sibs, born of consanguineous Iranian parents (family 5), with cerebellar ataxia, brain abnormalities, and cardiac conduction defects (CABAC; 619576), Beheshtian et al. (2019) identified a homozygous missense mutation in the EXOSC5 gene (T114I; 606492.0001). The mutation was found by exome sequencing; functional studies of the variant and studies of patient cells were not performed. The family had previously been reported by Hu et al. (2019) as family M8700013.
In 4 patients from 3 unrelated families with CABAC, Slavotinek et al. (2020) identified homozygous or compound heterozygous mutations in the EXOSC5 gene (606492.0001-606492.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing or microarray analysis, segregated with the disorder in the families. In vitro immunoprecipitation studies showed that 2 EXOSC5 missense mutations (T114I and L206H) caused altered interactions with other RNA exosome subunits. Studies of the orthologous mutations in budding yeast resulted in both impaired growth (L206H) or no growth defects (T114I), suggesting that the mutations may have distinct mechanistic consequences. Slavotinek et al. (2020) concluded that alteration of the RNA exosome could be tissue-specific, potentially underlying diverse clinical presentations.
In 2 sibs of Mexican descent with CABAC, Calame et al. (2021) identified compound heterozygous missense mutations in exon 3 of the EXOSC5 gene: T114I and T101K (606492.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.
Slavotinek et al. (2020) found that complete knockdown of the zebrafish exosc5 ortholog did not result in viable larvae. Larvae injected with a construct targeting exon 2 of exosc5 showed increased tail curvature, shortening of the tail and body, edema, small eyes and head, abnormal brain morphology, and fin defects. The findings suggested a critical role for EXOSC5 in neurodevelopment.
In 3 sibs, born of consanguineous Iranian parents (family 5), with cerebellar ataxia, brain abnormalities, and cardiac conduction defects (CABAC; 619576), Beheshtian et al. (2019) identified a homozygous c.341C-T transition (c.341C-T, NM_020158.4) in the EXOSC5 gene, resulting in a thr114-to-ile (T114I) substitution. The mutation was found by exome sequencing; functional studies of the variant and studies of patient cells were not performed. The family had previously been reported by Hu et al. (2019) as family M8700013.
In a 10-year-old girl (patient 1), born of unrelated parents, with CABAC, Slavotinek et al. (2020) identified compound heterozygous mutations in the EXOSC5 gene: a T114I (c.341C-T) substitution, and a 1,023-bp deletion (606492.0002), resulting in the deletion of exons 5 and 6. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing or microarray analysis, segregated with the disorder in the family. The c.341C-T variant was found at a low frequency in the gnomAD database (17 of 232,236 alleles, overall frequency of 7.32 x 10(-5)) and had a frequency of 0.06% among Latinos in ExAC. The deletion had not been reported in public databases. In addition, Slavotinek et al. (2020) reported 2 sibs (patients 4 and 5) with the disorder who were compound heterozygous for T114I and a frameshift mutation (606492.0004). In vitro immunoprecipitation studies showed that the T114I mutation caused altered interactions with other RNA exosome subunits; however, the mutation did not cause growth defects in yeast.
In 2 sibs of Mexican descent with CABAC, Calame et al. (2021) identified compound heterozygous missense mutations in exon 3 of the EXOSC5 gene: T114I and T101K (606492.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the 1,023-bp deletion (g.41,892,557_41,893,580del, GRCh37) in the EXOSC5 gene, resulting in the deletion of exons 5 and 6, that was found in compound heterozygous state in a patient with cerebellar ataxia, brain abnormalities, and cardiac conduction defects (CABAC; 619576) by Slavotinek et al. (2020), see 606492.0001.
In an 11-month-old boy (patient 2), born of consanguineous Iraqi parents, with cerebellar ataxia, brain abnormalities, and cardiac conduction defects (CABAC; 619576), Slavotinek et al. (2020) identified a homozygous c.617T-A transversion (c.617T-A, NM_020158.3) in the EXOSC5 gene, resulting in a leu206-to-his (L206H) substitution at a conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. In vitro immunoprecipitation studies showed that the mutation caused altered interactions with other RNA exosome subunits, and functional expression studies showed that the mutation caused growth defects in yeast.
In 2 sibs (patients 4 and 5) with cerebellar ataxia, brain abnormalities, and cardiac conduction defects (CABAC; 619576), Slavotinek et al. (2020) identified compound heterozygous mutations in the EXOSC5 gene: a 1-bp deletion (c.87del, NM_020158.3), predicted to result in a frameshift and premature termination (His30ThrfsTer35), and T114I (606492.0001). The mutations, which were found by exome sequencing, segregated with the disorder in the family. The frameshift mutation was not present in the gnomAD database.
In 2 sibs of Mexican descent with cerebellar ataxia, brain abnormalities, and cardiac conduction defects (CABAC; 619576), Calame et al. (2021) identified compound heterozygous missense mutations in exon 3 of the EXOSC5 gene: a c.302C-A transversion (c.302C-A, NM_020158.4), resulting in a thr101-to-lys (T101K) substitution at a conserved residue, and T114I (606492.0001). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The T101K variant was present in the heterozygous state in 8 individuals in the gnomAD database. Functional studies of the variants and studies of patient cells were not performed.
Beheshtian, M., Fattahi, Z., Fadaee, M., Vazehan, R., Jamali, P., Parsimehr, E., Kamgar, M., Zonooz, MF., Mahdavi, SS., Kalhor, Z., Arzhangi, S., Abedini, S. S., Kermani, F. S., Mojahedi, F., Kalscheuer, V. M., Ropers, H.-H., Kariminejad, A., Najmabadi, H., Kahrizi, K. Identification of disease-causing variants in the EXOSC gene family underlying autosomal recessive intellectual disability in Iranian families. Clin. Genet. 95: 718-725, 2019. [PubMed: 30950035] [Full Text: https://doi.org/10.1111/cge.13549]
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]
Calame, D. G., Herman, I., Fatih, J. M., Du, H., Akay, G., Jhangiani, S. N., Coban-Akdemir, Z., Milewicz, D. M., Gibbs, R. A., Posey, J. E., Marafi, D., Hunter, J. V., Fan, Y., Lupski, J. R., Miyake, C. Y. Risk of sudden cardiac death in EXOSC5-related disease. Am. J. Med. Genet. 185A: 2532-2540, 2021. [PubMed: 34089229] [Full Text: https://doi.org/10.1002/ajmg.a.62352]
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.
Hu, H., Kahrizi, K., Musante, L., Fattahi, Z., Herwig, R., Hosseini, M., Oppitz, C., Abedini, S. S., Suckow, V., Larti, F., Beheshtian, M., Lipkowitz, B. Genetics of intellectual disability in consanguineous families. Molec. Psychiat. 24: 1027-1039, 2019. [PubMed: 29302074] [Full Text: https://doi.org/10.1038/s41380-017-0012-2]
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]
Slavotinek, A., Misceo, D., Htun, S., Mathisen, L., Frengen, E., Foreman, M., Hurtig, J. E., Enyenihi, L., Sterrett, M. C., Leung, S. W., Schneidman-Duhovny, D., Estrada-Veras, J., and 11 others. Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness. Hum. Molec. Genet. 29: 2218-2239, 2020. [PubMed: 32504085] [Full Text: https://doi.org/10.1093/hmg/ddaa108]