Alternative titles; symbols
HGNC Approved Gene Symbol: ANAPC1
SNOMEDCT: 1003922004;
Cytogenetic location: 2q13 Genomic coordinates (GRCh38) : 2:111,766,231-111,884,193 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q13 | Rothmund-Thomson syndrome, type 1 | 618625 | Autosomal recessive | 3 |
ANAPC1 is 1 of several subunits of the anaphase-promoting complex (APC), which functions at the metaphase-to-anaphase transition of the cell cycle and is regulated by spindle checkpoint proteins. The APC is an E3 ubiquitin ligase that targets cell cycle regulatory proteins for degradation by the proteasome, thereby allowing progression through the cell cycle (summary by Jorgensen et al., 2001).
By PCR of a HeLa cell cDNA library using oligonucleotides matching the mouse Apc1 sequence, Jorgensen et al. (2001) cloned ANAPC1, which they called APC1. The deduced protein contains a repetitive region with at least 4 repeat domains predicted to fold into successive alpha/beta elements and form a horseshoe-like structure. Flanking the repetitive region are 2 Pfam-B domains. Mouse and human ANAPC1 share 92% amino acid identity, including 99% identity within the repetitive region. Northern blot analysis detected ANAPC1 expression in most tissues and cancer cell lines examined. Western blot analysis of mouse fibroblasts and HeLa cells detected ANAPC1 at an apparent molecular mass of more than 200 kD.
Jorgensen et al. (2001) determined that the ANAPC1 gene contains 42 exons and spans more than 206 kb.
By somatic cell hybrid analysis, FISH, and radiation hybrid analysis, Jorgensen et al. (2001) mapped the ANAPC1 gene to chromosome 2q13.
Yang et al. (2009) found that the major mitotic E3 ubiquitin ligase Cdc20 (603618)-anaphase-promoting complex (Cdc20-APC) regulates presynaptic differentiation in primary postmitotic mammalian neurons and in the rat cerebellar cortex. Cdc20-APC triggered the degradation of the transcription factor NeuroD2 (601725) and thereby promoted presynaptic differentiation. The NeuroD2 target gene encoding complexin-2 (CPLX2; 605033), which acts locally at presynaptic sites, mediated the ability of NeuroD2 to suppress presynaptic differentiation. Yang et al. (2009) concluded that their findings defined a Cdc20-APC ubiquitin signaling pathway that governs presynaptic development.
In 10 patients from 7 families with Rothmund-Thomson syndrome (RTS1; 618625), Ajeawung et al. (2019) identified homozygosity or compound heterozygosity for mutations in the ANAPC1 gene (see, e.g., 608473.0001-608473.0003).
In 5 female patients from 4 families (families 1-4) with Rothmund-Thomson syndrome (RTS1; 618625), including 3 Amish families, Ajeawung et al. (2019) identified homozygosity for a C-T transition (c.2705-198C-T, NM_022662.3) in intron 22 of the ANAPC1 gene. In 5 male patients with RTS from 3 more families, they identified compound heterozygosity for the intronic mutation and another mutation in the ANAPC1 gene, including a 1-bp duplication (c.1778dupA; 608473.0002) in 2 brothers (family 6) and an intronic mutation (c.4373+1G-A; 608473.0003) in another pair of brothers (family 7). The mutations were present in heterozygosity in the respective parents. Immunoblot analysis in fibroblasts from 2 of the Amish patients (families 2 and 3) showed decreased ANAPC1 protein levels compared to controls. Further analysis of fibroblasts from 1 of the affected sisters in family 3 showed that the mutation in intron 22 causes the activation of a 95-bp pseudoexon, resulting in mRNAs with premature termination codons and nonsense-mediated decay. Real-time cell microscopy revealed a significant delay within interphase for synchronized fibroblast cells derived from affected individuals from families 2 and 3 compared to control fibroblasts.
For discussion of the 1-bp duplication (c.1778dupA, NM_022662.3) in exon 15 of the ANAPC1 gene, causing a frameshift predicted to result in a premature termination codon (Asn593LysfsTer9), that was found in compound heterozygous state in 2 brothers (family 6) with Rothmund-Thomson syndrome (RTS1; 618625) by Ajeawung et al. (2019), see 608473.0001.
For discussion of the G-A transition (c.4373+1G-A, NM_022662.3) in intron 35 of the ANAPC1 gene that was found in compound heterozygous state in 2 brothers (family 7) with Rothmund-Thomson syndrome (RTS1; 618625) by Ajeawung et al. (2019), see 608473.0001.
Ajeawung, N. F., Nguyen, T. T. M., Lu, L., Kucharski, T. J., Rousseau, J., Molidperee, S., Atienza, J., Gamache, I., Jin, W., Plon, S. E., Lee, B. H., Teodoro, J. G., Wang, L. L., Campeau, P. M. Mutations in ANAPC1, encoding a scaffold subunit of the anaphase-promoting complex, cause Rothmund-Thomson syndrome type 1. Am. J. Hum. Genet. 105: 625-630, 2019. [PubMed: 31303264] [Full Text: https://doi.org/10.1016/j.ajhg.2019.06.011]
Jorgensen, P. M., Graslund, S., Betz, R., Stahl, S., Larsson, C., Hoog, C. Characterisation of the human APC1, the largest subunit of the anaphase-promoting complex. Gene 262: 51-59, 2001. [PubMed: 11179667] [Full Text: https://doi.org/10.1016/s0378-1119(00)00511-4]
Yang, Y., Kim, A. H., Yamada, T., Wu, B., Bilimoria, P. M., Ikeuchi, Y., de la Iglesia, N., Shen, J., Bonni, A. A Cdc20-APC ubiquitin signaling pathway regulates presynaptic differentiation. Science 326: 575-578, 2009. [PubMed: 19900895] [Full Text: https://doi.org/10.1126/science.1177087]