Alternative titles; symbols
HGNC Approved Gene Symbol: ASCC1
Cytogenetic location: 10q22.1 Genomic coordinates (GRCh38): 10:72,096,032-72,217,134 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.1 | Barrett esophagus/esophageal adenocarcinoma | 614266 | 3 | |
| Spinal muscular atrophy with congenital bone fractures 2 | 616867 | Autosomal recessive | 3 |
The ASCC1 gene encodes a subunit of the tetrameric ASC-1 transcriptional cointegrator complex. The other subunits include TRIP4 (ASC1; 604501), ASCC2 (614216), and ASCC3 (614217). The complex associates with transcription factors or with nuclear receptors and can bidirectionally affect the link between receptor and transcription machinery, either as corepressor or coactivator. This complex also likely participates in pre-mRNA processing and regulation of splicing (summary by Knierim et al., 2016).
By sequencing peptides that copurified with the 650-kD ASC1 (TRIP4; 604501) complex from HeLa cells, followed by database analysis and PCR of a HeLa cell cDNA library, Jung et al. (2002) cloned ASCC1, which they designated p50. The deduced 357-amino acid protein contains a KH-type RNA-binding motif near its N terminus. Northern blot analysis detected variable expression of an approximately 2.1-kb transcript in all tissues examined. P50 localized to both nuclei and cytoplasm of HeLa cells. Database analysis revealed orthologs of p50 in mouse, fly, frog, and nematode.
Knierim et al. (2016) found ubiquitous expression of the Ascc1 gene in mouse embryos. Highest expression was seen in dorsal root ganglia, the paraspinal sympathetic and trigeminal ganglia, and thyroid and submandibular glands, as well as the spinal cord. Expression in the cerebral cortex was comparable to the expression in the spinal cord.
Hartz (2011) mapped the ASCC1 gene to chromosome 10q22.1 based on an alignment of the ASCC1 sequence (GenBank AF132952) with the genomic sequence (GRCh37).
Jung et al. (2002) identified a 650-kD protein complex containing ASC1, p50, p100 (ASCC2; 614216), and p200 (ASCC3; 614217). Immunodepletion of p50 from HeLa cell nuclear extracts almost completely eliminated phorbol ester-induced AP1 (see 165160) transactivation of a reporter gene. Yeast 2-hybrid analysis, coimmunoprecipitation of in vitro-translated proteins, and protein pull-down experiments confirmed direct interaction between p50 and p200. Domain analysis revealed that the KH motif of p50 was required its interaction with p200.
Gastrin (GAS; 137250) regulates the expression of a variety of genes involved in the control of acid secretion. It also triggers tissue response to damage, infection, and inflammation in cells expressing gastrin receptor (CCKBR; 118445) and, indirectly, in nearby cells via a paracrine mechanism. Almeida-Vega et al. (2009) found that gastrin directly induced upregulation of the antiapoptotic regulator PAI2 (SERPINB2; 173390) in CCKBR-positive cells. CCKBR-positive cells also released IL8 (146930) and prostaglandin E2 into the culture medium in response to gastrin, which resulted in elevated PAI2 expression in cocultured CCKBR-negative cells. IL8 signaling in CCKBR-negative cells upregulated PAI2 via binding of the ASC1 complex to the PAI2 promoter. Prostaglandin E2 independently upregulated PAI2 via RHOA (165390)-dependent signaling that induced binding of MAZ (600999) to the PAI2 promoter. Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis revealed that MAZ and the p50 subunit of the ASC1 complex bound directly to sites in the PAI2 promoter. Mutation of the putative MAZ site in the PAI2 promoter reduced responses to RHOA. Knockdown of the p50 or p65 (TRIP4) subunits of the ASC1 complex via small interfering RNA significantly reduced PAI2 upregulation in response to gastrin.
In immunoprecipitation studies, Knierim et al. (2016) identified CSRP1 (123876) as a binding partner of the ASC1 holocomplex. An interaction with SRF (600589) was not detected.
By sequencing 158 regulators of the NF-kappa-B (see 164011) pathway in patients with rheumatoid arthritis (RA; 180300), Torices et al. (2015) identified a 233C-G SNP in the ASCC1 gene that introduced a stop codon at ser78 (S78X; rs11000217). The SNP showed similar distributions in RA patients and controls and was not associated with RA susceptibility. Reporter gene assays in multiple cell lines showed that human ASCC1 inhibited NF-kappa-B transcriptional activity and expression of the NF-kapp-B target genes TRAIL (TNFSF10; 603598), TNF (191160), CIAP1 (BIRC2; 601712), and IL8. The S78X variant, which led to deletion of all predicted protein domains of ASCC1, lacked the NF-kappa-B inhibitory activity of the full-length protein. Torices et al. (2015) concluded that ASCC1 is an inhibitor of NF-kappa-B activation and presented evidence suggesting that the S78X variant may play a role in RA disease severity.
Barrett Esophagus/Esophageal Adenocarcinoma
Orloff et al. (2011) identified a germline asn290-to-ser (N290S; 614215.0001) mutation in the ASCC1 gene in 2 (2.1%) of 116 patients of European descent with Barrett esophagus and/or esophageal adenocarcinoma (614266). The mutation was not found in 125 controls. This genomic region was studied after being identified by genomewide linkage analysis of 21 concordant and 11 discordant sib pairs with the disorders.
Spinal Muscular Atrophy With Congenital Bone Fractures 2
In 2 sisters, born of consanguineous Turkish parents, with spinal muscular atrophy with congenital bone fractures-2 (SMABF2; 616867) resulting in early death, Knierim et al. (2016) identified a homozygous truncating mutation in the ASCC1 gene (c.157dupG; 1614215.0002). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family.
In a female infant, born of unrelated Portuguese parents, with SMABF2, Oliveira et al. (2017) identified a homozygous c.157dupG mutation in the ASCC1 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, occurred in heterozygous state in each unaffected parent. Functional studies of the variant and studies of patient cells were not performed. Homozygosity mapping did not suggest high consanguinity, and the authors noted that the same mutation had been identified by Knierim et al. (2016) in a family of Middle Eastern descent.
In 6 patients from 3 unrelated families with SMABF2, Bohm et al. (2019) identified homozygous or compound heterozygous mutations in the ASCC1 gene (614215.0002-614215.0004). The mutations, which were found by direct Sanger sequencing and/or exome sequencing, segregated with the disorder in the families from whom parental DNA was available. Functional studies of the variants and studies of patient cells were not performed, but all variants were predicted to result in nonsense-mediated mRNA decay and a loss of function.
In a stillborn infant, born of unrelated Italian parents, with SMABF2, Giuffrida et al. (2020) identified compound heterozygous mutations in the ASCC1 gene (614215.0005 and 614215.0006). The mutations, which were found by microarray analysis and exome sequencing and confirmed by RT-PCR and Sanger sequencing, were each inherited from an unaffected parent. Functional studies of the variants and studies of patient cells were not performed, but both variants were predicted to result in a loss of protein function.
Knierim et al. (2016) found that mopholino knockdown of the ascc1 gene in zebrafish embryos resulted in a severe impairment of axonal outgrowth of alpha-motoneurons, as well as impaired formation of the neuromuscular junction and organization of the myotome. Mutant zebrafish showed compromised motor responses.
Orloff et al. (2011) identified a germline 869G-A transition in exon 8 of the ASCC1 gene, resulting in an asn290-to-ser (N290S) substitution, in 2 (2.1%) of 116 patients of European descent with Barrett esophagus and/or esophageal adenocarcinoma (614266). The mutation was not found in 125 controls. This genomic region was studied after being identified by genomewide linkage analysis of 21 concordant and 11 discordant sib pairs with the disorders.
In 2 sisters (family D), born of consanguineous Turkish parents, with spinal muscular atrophy with congenital bone fractures-2 (SMABF2; 616867), Knierim et al. (2016) identified a homozygous 1-bp duplication (c.157dupG, NM_001198800.2) in exon 3 of the ASCC1 gene, resulting in a frameshift and premature termination (Glu53GlyfsTer19). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The mutation was found in 2 of 120,662 alleles in the ExAC database. Patient fibroblasts showed complete absence of the ASCC1 protein. Mutant mRNA was unable to rescue the motor defects in morpholino-knockout zebrafish embryos.
In a female infant, born of unrelated Portuguese parents, with SMABF2, Oliveira et al. (2017) identified a homozygous c.157dupG mutation in the ASCC1 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, occurred in heterozygous state in each unaffected parent. Functional studies of the variant and studies of patient cells were not performed. Homozygosity mapping did not suggest high consanguinity, and the authors noted that the same mutation had been identified by Knierim et al. (2016) in a family of Middle Eastern descent.
In 2 sibs, born of consanguineous parents (family 1 of Tunisian descent), with SMABF2, Bohm et al. (2019) identified homozygosity for the c.157dupG mutation in exon 3a of the ASCC1 gene. The mutation was found by direct Sanger sequencing; DNA from the unaffected parents was not available. An affected girl from a second unrelated family (family 2 of Moroccan descent) was compound heterozygous for c.157dupG and a c.466C-T transition in exon 5, resulting in an arg156-to-ter (R156X; 614215.0003) substitution. The R156X variant, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both variants were found at a low frequency in heterozygous state in the gnomAD database (8 alleles for c.157dupG and 4 alleles for R156X). Functional studies of the variants and studies of patient cells were not performed, but both variants were predicted to result in nonsense-mediated mRNA decay and a loss of function. Bohm et al. (2019) noted that exon 3a is expressed in muscle tissue, whereas exon 3b is not.
For discussion of the c.466C-T transition (c.466C-T, NM_001198799.2) in exon 5 of the ASCC1 gene, resulting in an arg156-to-ter (R156X) substitution, that was found in compound heterozygous state in a patient with spinal muscular atrophy with congenital bone fractures-2 (SMABF2; 616867) by Bohm et al. (2019), see 614215.0002.
In 3 sibs, born of consanguineous parents (family 3 of Sri Lankan descent), with spinal muscular atrophy with congenital bone fractures-2 (SMABF2; 616867), Bohm et al. (2019) identified a homozygous c.412C-T transition (c.412C-T, NM_001198799.2) in exon 5 of the ASCC1 gene, resulting in an arg138-to-ter (R138X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was found at a low frequency in heterozygous state in the gnomAD database (4 alleles). Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in nonsense-mediated mRNA decay and a loss of function.
In a stillborn infant, born of unrelated Italian parents, with spinal muscular atrophy with congenital bone fractures-2 (SMABF2; 616867), Giuffrida et al. (2020) identified compound heterozygous mutations in the ASCC1 gene: a 64-kb deletion, predicted to result in an intragenic in-frame deletion of exons 6 through 9a, which includes part of the protein kinase A anchor protein/nuclear localization signal domain, and a c.1027C-T transition in exon 9a, resulting in an arg343-to-ter (R343X; 614215.0006) substitution. The mutations, which were found by microarray analysis and exome sequencing and confirmed by RT-PCR and Sanger sequencing, were each inherited from an unaffected parent. The R343X variant was not found in the gnomAD, ExAC, or Exome Sequencing Project databases. Functional studies of the variants and studies of patient cells were not performed, but both variants were predicted to result in a loss of protein function.
For discussion of the c.1027C-T transition (c.1027C-T, NM_001198799.2) in exon 9a of the ASCC1 gene, resulting in an arg343-to-ter (R343X) substitution, that was found in compound heterozygous state in a patient with spinal muscular atrophy with congenital bone fractures-2 (SMABF2; 616867) by Giuffrida et al. (2020), see 614215.0005.
Almeida-Vega, S., Catlow, K., Kenny, S., Dimaline, R., Varro, A. Gastrin activates paracrine networks leading to induction of PAI-2 via MAZ and ASC-1. Am. J. Physiol. Gastrointest. Liver Physiol. 296: G414-G423, 2009. [PubMed: 19074642] [Full Text: https://doi.org/10.1152/ajpgi.90340.2008]
Bohm, J., Malfatti, E., Oates, E., Jones, K., Brochier, G., Boland, A., Deleuze, J.-F., Romero, N. B., Laporte, J. Novel ASCC1 mutations causing prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures. J. Med. Genet. 56: 617-621, 2019. [PubMed: 30327447] [Full Text: https://doi.org/10.1136/jmedgenet-2018-105390]
Giuffrida, M. G., Mastromoro, G., Guida, V., Truglio, M., Fabbretti, M., Torres, B., Mazza, T., De Luca, A., Roggini, M., Bernardini, L., Pizzuti, A. A new case of SMABF2 diagnosed in stillbirth expands the prenatal presentation and mutational spectrum of ASCC1. Am. J. Med. Genet. 182A: 508-512, 2020. [PubMed: 31880396] [Full Text: https://doi.org/10.1002/ajmg.a.61431]
Hartz, P. A. Personal Communication. Baltimore, Md. 9/6/2011.
Jung, D.-J., Sung, H.-S., Goo, Y.-W., Lee, H. M., Park, O. K., Jung, S.-Y., Lim, J., Kim, H.-J., Lee, S.-K., Kim, T. S., Lee, J. W., Lee, Y. C. Novel transcription coactivator complex containing activating signal cointegrator 1. Molec. Cell. Biol. 22: 5203-5211, 2002. [PubMed: 12077347] [Full Text: https://doi.org/10.1128/MCB.22.14.5203-5211.2002]
Knierim, E., Hirata, H., Wolf, N. I., Morales-Gonzalez, S., Schottmann, G., Tanaka, Y., Rudnik-Schoneborn, S., Orgeur, M., Zerres, K., Vogt, S., van Riesen, A., Gill, E., and 9 others. Mutations in subunits of the activating signal cointegrator 1 complex are associated with prenatal spinal muscular atrophy and congenital bone fractures. Am. J. Hum. Genet. 98: 473-489, 2016. [PubMed: 26924529] [Full Text: https://doi.org/10.1016/j.ajhg.2016.01.006]
Oliveira, J., Martins, M., Pinto Leite, R., Sousa, M., Santos, R. The new neuromuscular disease related with defects in the ASC-1 complex: report of a second case confirms ASCC1 involvement. Clin. Genet. 92: 434-439, 2017. [PubMed: 28218388] [Full Text: https://doi.org/10.1111/cge.12997]
Orloff, M., Peterson, C., He, X., Ganapathi, S., Heald, B., Yang, Y., Bebek, G., Romigh, T., Song, J. H., Wu, W., David, S., Cheng, Y., Meltzer, S. J., Eng, C. Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma. JAMA 306: 410-419, 2011. [PubMed: 21791690] [Full Text: https://doi.org/10.1001/jama.2011.1029]
Torices, S., Alvarez-Rodriguez, L., Grande, L., Varela, I., Munoz, P., Pascual, D., Balsa, A., Lopez-Hoyos, M., Martinez-Taboada, V., Fernandez-Luna, J. L. A truncated variant of ASCC1, a novel inhibitor of NF-kappa-B, is associated with disease severity in patients with rheumatoid arthritis. J. Immun. 195: 5415-5420, 2015. [PubMed: 26503956] [Full Text: https://doi.org/10.4049/jimmunol.1501532]