Alternative titles; symbols
HGNC Approved Gene Symbol: EXOSC9
Cytogenetic location: 4q27 Genomic coordinates (GRCh38) : 4:121,801,323-121,817,021 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q27 | Pontocerebellar hypoplasia, type 1D | 618065 | Autosomal recessive | 3 |
The EXOSC9 gene encodes a subunit of the RNA exosome, a multiprotein complex that plays a vital role in gene expression via processing and degradation of mRNA. EXOSC9 helps form the core of the complex, a hexamer channel through which the RNA passes (summary by Burns et al., 2018).
Antinucleolar antibodies are found in patients with scleroderma or polymyositis or in patients with overlap of these 2 syndromes. The 2 most prominent proteins in this PMSCL autoantigen complex, PMSCL1 and PMSCL2 (605960), are detected as 75- and 100-kD molecules, respectively. Using human serum with predominant reactivity to the 75-kD PMSCL antigen to screen a T-cell lymphoblastic leukemia expression library, Alderuccio et al. (1991) obtained a cDNA encoding PMSCL1. The deduced 355-amino acid protein contains a high proportion of charged residues at its C terminus, including a string suggestive of a nuclear or nucleolar localization signal. Northern blot analysis revealed expression of a 1.6-kb PMSCL1 transcript in 2 leukemia cell lines. SDS-PAGE and immunoblot analysis showed that the recombinant protein is expressed at a size close to that of the native protein, which is considerably higher than the predicted size of 39 kD, probably due to acidic residues at the C terminus. Immunofluorescence, immunoblot, and immunoprecipitation analysis with rabbit or patient sera indicated nucleolar and nucleoplasmic expression.
Gross (2014) mapped the EXOSC9 gene to chromosome 4q27 based on an alignment of the EXOSC9 sequence (GenBank AK301967) with the genomic sequence (GRCh37).
In 4 unrelated patients of different ethnicities with pontocerebellar hypoplasia type 1D (PCH1D; 618065), Burns et al. (2018) identified homozygous or compound heterozygous mutations in the EXOSC9 gene. Three patients carried the same homozygous variant (L14P; 606180.0001), and haplotype analysis suggested a common ancestor. The fourth patient was compound heterozygous for L14P and a nonsense mutation (R161X; 606180.0002). The patient with the nonsense mutation had a more severe phenotype, with congenital fractures and death at age 15 months. RNA sequencing in fibroblasts and skeletal muscle derived from several patients showed significant changes in RNA metabolism and gene expression, particularly affecting genes involved in cellular and embryonic developmental processes of the neuronal system. Other genes affected including those involved in arthrogryposis and skeletal dysplasia or bone disease. However, EXOSC9 mRNA and mRNAs encoding other subunits of the exosome complex did not show a significant difference in expression. The findings suggested a loss of function of RNA processing by the exosome.
In 2 unrelated Emirati girls with PCH1D, who were both born to consanguineous parents, Bizzari et al. (2020) identified homozygosity for the L14P mutation in the EXOSC9 gene. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in both sets of parents.
In 3 patients with PCH1D, including 2 brothers from a nonconsanguineous Japanese family and a boy from a consanguineous Iranian family, Sakamoto et al. (2021) identified biallelic mutations in the EXOSC9 gene (606180.0003-606180.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were present in heterozygous state in both sets of parents.
Burns et al. (2018) found that knockdown of the exosc9 gene in zebrafish embryos resulted in brain abnormalities with absence of portions of the cerebellum and hindbrain, as well as abnormal motor neuron development and migration and abnormalities at the neuromuscular junction.
In 3 unrelated patients (individuals 1, 3, and 4) with pontocerebellar hypoplasia type 1D (PCH1D; 618065), Burns et al. (2018) identified a homozygous c.41T-C transition (NG_029848.1) in the EXOSC9 gene, resulting in a leu14-to-pro (L14P) substitution. The mutation in individual 1, who was a 28-month-old girl born of unrelated parents from El Salvador, was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing. Individual 3 was a 4.5-year-old girl born of consanguineous Saudi Arabian parents, and individual 4 was a 19-month-old girl born of unrelated parents of African, European, and Filipino ancestry. The mutation segregated with the disorder in all 3 families, and haplotype analysis suggested a common ancestor. The L14P variant was found 6 times in heterozygous state in the ExAC database in individuals of African descent (allele frequency of 4.947 x 10(-5)), but not in individuals of Hispanic descent. Another patient (individual 2), an unrelated boy of African, Canadian, and Jamaican descent who died at age 15 months, was compound heterozygous for L14P and a c.481C-T transition in the EXOSC9 gene, resulting in an arg161-to-ter (R161X; 606180.0002) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in this family. The R161X mutation was listed 3 times in heterozygous state in the ExAC database. Immunoblotting of cells from individuals 1 and 2 showed decreased levels of the EXOCS9 protein, suggesting instability or reduced assembly and function of the exosome complex.
In 2 unrelated Emirati girls with PCH1D, who were both born to consanguineous parents, Bizzari et al. (2020) identified homozygosity for a c.41T-C transition (c.41T-C, NM_001034194.1) in the EXOSC9 gene, resulting in a leu14-to-pro substitution. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in both sets of parents. The mutation was predicted to result in protein instability. The variant was present at an allele frequency of 0.00007 in the African population in the gnomAD database.
For discussion of the c.481C-T transition (NG_029848.1) in the EXOSC9 gene, resulting in an arg161-to-ter (R161X) substitution, that was found in compound heterozygous state in a patient with pontocerebellar hypoplasia type 1D (PCH1D; 618065) by Burns et al. (2018), see 606180.0001.
In 2 brothers with pontocerebellar hypoplasia type 1D (PCH1D; 618065), who were born to nonconsanguineous Japanese parents, Sakamoto et al. (2021) identified compound heterozygous mutations in the EXOSC9 gene: a c.239T-G transversion (c.239T-G, NM_001034194.1), resulting in a leu80-to-arg (L80R) substitution, and a 1-bp duplication (c.484dupA; 606180.0004), resulting in a frameshift predicted to lead to premature termination (Arg162LysfsTer3). The mutations were found by exome sequencing and confirmed by Sanger sequencing. The parents were shown to be carriers.
For discussion of the 1-bp duplication (c.484dupA, NM_001034194.1) in the EXOSC9 gene, resulting in a frameshift and predicted premature termination (Arg162LysfsTer3), that was found in compound heterozygous state in sibs with pontocerebellar hypoplasia type 1D (PCH1D; 618065) by Sakamoto et al. (2021), see 606180.0003.
In a boy with pontocerebellar hypoplasia type 1D (PCH1D; 618065), who was born to consanguineous Iranian parents, Sakamoto et al. (2021) identified a homozygous c.151G-C transversion (c.151G-C, NM_001034194.1) in the EXOSC9 gene, resulting in a gly51-to-arg substitution (G51R). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in his parents.
Alderuccio, F., Chan, E. K. L., Tan, E. M. Molecular characterization of an autoantigen of PM-Scl in the polymyositis/scleroderma overlap syndrome: a unique and complete human cDNA encoding an apparent 75-kD acidic protein of the nucleolar complex. J. Exp. Med. 173: 941-952, 1991. [PubMed: 2007859] [Full Text: https://doi.org/10.1084/jem.173.4.941]
Bizzari, S., Hamzeh, A. R., Mohamed, M., Al-Ali, M. T., Bastaki, F. Expanded PCH1D phenotype linked to EXOSC9 mutation. Europ. J. Med. Genet. 63: 103622, 2020. Note: Electronic Article. [PubMed: 30690203] [Full Text: https://doi.org/10.1016/j.ejmg.2019.01.012]
Burns, D. T., Donkervoort, S., Muller, J. S., Knierim, E., Bharucha-Goebel, D., Faqeih, E. A., Bell, S. K., Alfaifi, A. Y., Monies, D., Millan, F., Retterer, K., Dyack, S., and 18 others. Variants in EXOSC9 disrupt the RNA exosome and result in cerebellar atrophy with spinal motor neuronopathy. Am. J. Hum. Genet. 102: 858-873, 2018. [PubMed: 29727687] [Full Text: https://doi.org/10.1016/j.ajhg.2018.03.011]
Gross, M. B. Personal Communication. Baltimore, Md. 6/25/2014.
Sakamoto, M., Iwama, K., Sekiguchi, F., Mashimo, H., Kumada, S., Ishigaki, K., Okamoto, N., Behnam, M., Ghadami, M., Koshimizu, E., Miyatake, S., Mitsuhashi, S., Mizuguchi, T., Takata, A., Saitsu, H., Miyake, N., Matsumoto, N. Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy. J. Hum. Genet. 66: 401-407, 2021. [PubMed: 33040083] [Full Text: https://doi.org/10.1038/s10038-020-00853-2]