Alternative titles; symbols
HGNC Approved Gene Symbol: PPP2R1A
SNOMEDCT: 1254650002;
Cytogenetic location: 19q13.41 Genomic coordinates (GRCh38) : 19:52,190,052-52,229,518 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.41 | Houge-Janssens syndrome 2 | 616362 | Autosomal dominant | 3 |
The PR65/A regulatory subunit of protein phosphatase-2A (PP2A) serves as a scaffolding molecule that coordinates the assembly of the catalytic subunit, PPP2CA (176915), and a variable regulatory B subunit to generate functionally diverse heterotrimers. The PR65/A subunit exists as 2 isoforms, PPP2R1A and PPP2R1B (603113) (Groves et al., 1999).
Hemmings et al. (1990) cloned the cDNA corresponding to the PPP2R1A gene, encoding the alpha isoform of the 65-kD structural/regulatory subunit A of the PP2A holoenzyme. The PPP2R1A gene has 86% identity with the PPP2R1B gene, as demonstrated by Hendrix et al. (1993).
Everett et al. (1999) showed that expression of all 3 subunits of PP2A, including Ppp2r1a, is regulated in a cell-specific and developmentally stage-specific manner in rat kidney, with the highest levels of enzyme activity present in the nephrogenic cortex of fetal kidney.
Using a yeast 2-hybrid assay, Lubert and Sarge (2003) showed that mouse importin-9 (IPO9, or IMP9; 620893) interacted specifically with Pr65, the A subunit of PP2A. The authors confirmed the interaction by in vitro pull down, immunoprecipitation, and microcystin-sepharose chromatography. Further analysis showed that interaction of Imp9 with Pr65 was important for PP2A function during nuclear import.
To explore the genetic origin of ovarian clear cell carcinoma (167000), Jones et al. (2010) determined the exomic sequences of 8 tumors after immunoaffinity purification of cancer cells. Through comparative analyses of normal cells from the same patients, Jones et al. (2010) identified 4 genes that were mutated in at least 2 tumors. Two of these genes, PPP2R1A and ARID1A (603024), which encodes a protein that participates in chromatin remodeling, were not known to be involved in ovarian clear cell carcinoma. The other 2 genes, PIK3CA (171834) and KRAS (190070), had previously been implicated in ovarian clear cell carcinoma. The nature and pattern of the mutations suggested that PPP2R1A functions as an oncogene and ARID1A as a tumor-suppressor gene. In a total of 42 ovarian clear cell carcinomas, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A. Jones et al. (2010) concluded that their results suggested that aberrant chromatin remodeling contributes to the pathogenesis of ovarian clear cell carcinoma.
Groves et al. (1999) reported that the crystal structure of the PPP2R1A subunit at 2.3-angstrom resolution revealed the conformation of its 15 tandemly repeated 'heat' sequences, degenerate motifs of 39 amino acids present in a variety of proteins, including huntingtin (HTT; 613004) and importin-beta (see 602738). Individual motifs are composed of a pair of antiparallel alpha-helices that assemble in a mainly linear, repetitive fashion to form an elongated molecule characterized by a double layer of alpha-helices. The protein interaction interface is formed from the intrarepeat turns that are aligned to form a continuous ridge.
Ruteshouser et al. (2001) found that the PPP2R1A gene consists of 15 exons, spanning a region 36 kb in length.
The PPP2R1A gene is located on chromosome 19q13.4 (Ruteshouser et al., 2001).
The Deciphering Developmental Disorders Study (2015) identified 3 patients with Houge-Janssens syndrome-2 (HJS2; 616362) who had missense mutations in the PPP2R1A gene (R182W, 605983.0001; P179L, 605983.0002). No functional studies were performed.
In 2 unrelated patients with HJS2, Houge et al. (2015) identified 2 different de novo heterozygous missense mutations in the PPP2R1A gene (605983.0001 and 605983.0003). The mutations were found by parent-child trio exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that all 3 reported PPP2R1A mutations affected PP2A holoenzyme formation by variably interfering with interaction of the A-alpha subunit with the C subunit. All mutations resulted in decreased phosphatase activity, consistent with a dominant-negative effect.
In 2 unrelated girls with Houge-Janssens syndrome-2 (HJS2; 616362), the Deciphering Developmental Disorders Study (2015) identified a heterozygous C-to-T transition at chromosome coordinate g.52,715,979 (chr19.52,715,979C-T, GRCh37) in the PPP2R1A gene, resulting in an arg182-to-trp (R182W) substitution. This mutation occurred as a de novo event in both patients. No functional studies were performed.
In a patient with MRD36, Houge et al. (2015) identified a de novo heterozygous c.544C-T transition (c.544C-T, NM_014225.5) in the PPP2R1A gene that resulted in a R182W substitution.
In a girl with Houge-Janssens syndrome-2 (HJS2; 616362), the Deciphering Developmental Disorders Study (2015) identified a heterozygous C-to-T transition at chromosome coordinate g.52,715,971 (chr19.52,715,971C-T, GRCh37) in the PPP2R1A gene, resulting in a pro179-to-leu (P179L) substitution. This mutation occurred as a de novo event. No functional studies were performed.
In a patient with Houge-Janssens syndrome-2 (HJS2; 616362), Houge et al. (2015) identified a de novo heterozygous c.773G-A transition (c.773G-A, NM_014225.5) in the PPP2R1A gene, resulting in an arg258-to-his (R258H) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing.
Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519: 223-228, 2015. [PubMed: 25533962] [Full Text: https://doi.org/10.1038/nature14135]
Everett, A. D., Xue, C., Stoops, T. Developmental expression of protein phosphatase 2A in the kidney. J. Am. Soc. Nephrol. 10: 1737-1745, 1999. [PubMed: 10446941] [Full Text: https://doi.org/10.1681/ASN.V1081737]
Groves, M. R., Hanlon, N., Turowski, P., Hemmings, B. A., Barford, D. The structure of the protein phosphatase 2A PR65/A subunit reveals the conformation of its 15 tandemly repeated HEAT motifs. Cell 96: 99-110, 1999. [PubMed: 9989501] [Full Text: https://doi.org/10.1016/s0092-8674(00)80963-0]
Hemmings, B. A., Adams-Pearson, C., Maurer, F., Muller, P., Goris, J., Merlevede, W., Hofsteenge, J., Stone, S. R. Alpha- and beta-forms of the 65-kDa subunit of protein phosphatase 2A have a similar 39 amino acid repeating structure. Biochemistry 29: 3166-3173, 1990. [PubMed: 2159327] [Full Text: https://doi.org/10.1021/bi00465a002]
Hendrix, P., Turowski, P., Mayer-Jaekel, R. E., Goris, J., Hofsteenge, J., Merlevede, W., Hemmings, B. A. Analysis of subunit isoforms in protein phosphatase 2A holoenzymes from rabbit and Xenopus. J. Biol. Chem. 268: 7330-7337, 1993. [PubMed: 7681822]
Houge, G., Haesen, D., Vissers, L. E. L. M., Mehta, S., Parker, M. J., Wright, M., Vogt, J., McKee, S., Tolmie, J. L., Cordeiro, N., Kleefstra, T., Willemsen, M. H., and 17 others. B56-delta-related protein phosphatase 2A dysfunction identified in patients with intellectual disability. J. Clin. Invest. 125: 3051-3062, 2015. [PubMed: 26168268] [Full Text: https://doi.org/10.1172/JCI79860]
Jones, S., Wang, T.-L., Shih, I.-M., Mao, T.-L., Nakayama, K., Roden, R., Glas, R., Slamon, D., Diaz, L. A., Jr., Vogelstein, B., Kinzler, K. W., Velculescu, V. E., Papadopoulos, N. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330: 228-231, 2010. [PubMed: 20826764] [Full Text: https://doi.org/10.1126/science.1196333]
Lubert, E. J., Sarge, K. D. Interaction between protein phosphatase 2A and members of the importin beta superfamily. Biochem. Biophys. Res. Commun. 303: 908-913, 2003. [PubMed: 12670497] [Full Text: https://doi.org/10.1016/s0006-291x(03)00434-0]
Ruteshouser, E. C., Ashworth, L. K., Huff, V. Absence of PPP2R1A mutations in Wilms tumor. Oncogene 20: 2050-2054, 2001. [PubMed: 11360189] [Full Text: https://doi.org/10.1038/sj.onc.1204301]