Alternative titles; symbols
HGNC Approved Gene Symbol: PPP2R2B
SNOMEDCT: 719208005;
Cytogenetic location: 5q32 Genomic coordinates (GRCh38) : 5:146,580,742-147,081,520 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q32 | Spinocerebellar ataxia 12 | 604326 | Autosomal dominant | 3 |
The PPP2R2B gene encodes a brain-specific regulatory subunit B of protein phosphatase 2. Protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine phosphatase, has been implicated in a variety of regulatory processes, including cell growth and division, muscle contraction, and gene transcription. PP2A is composed of a 36-kD catalytic subunit (176915), a highly homologous 65-kD structural subunit (176915), and any of several different regulatory subunits that control its specificity, including PPP2R2B (Mayer et al., 1991).
By screening lung fibroblast and fetal brain cDNA libraries using 2 overlapping oligonucleotides corresponding to a tryptic peptide derived from the 55-kD subunit of rabbit PP2A (PR55), Mayer et al. (1991) isolated human cDNAs encoding PPP2R2A (604941) and PPP2R2B, which they termed PR55-alpha and PR55-beta, respectively. Sequence analysis indicated that the PPP2R2B gene encodes a deduced 443-amino acid protein of approximately 52 kD. The nucleotide sequence of PPP2R2B is 75% identical to PPP2R2A in the coding region. Northern blot analysis detected strong expression of an approximately 2.5-kb PPP2R2A transcript in a neuroblastoma cell line but weak or no expression in other neuroblastoma and tumor cell lines.
Using deletion/site-directed mutagenesis, cDNA overexpression assays, DNA pull-down and chromatin immunoprecipitation assays, and in silico analysis, Lin et al. (2010) found that CREB1 (123810) and SP1 (189906) upregulate PPP2R2B expression by binding to conserved sequences upstream of the polymorphic CAG repeat site, whereas TFAP4 (600743) binds downstream of the CAG repeats to downregulate PPP2R2B expression. The CAG repeats themselves also function as a cis element to upregulate PPP2R2B expression.
Schols et al. (1997) identified a novel form of autosomal dominant spinocerebellar ataxia (SCA), termed SCA12 (604326), in a large pedigree, 'R,' of German descent. The phenotype was variable, but the prototypic phenotype was that of a classic spinocerebellar ataxia, and the disease resembled the spinocerebellar ataxias more closely than any other form of neurodegenerative disorder. Holmes et al. (1999) used repeat expansion detection (RED), as described by Schalling et al. (1993), to identify an expanded CAG repeat (604325.0001) in the proband and other affected family members with SCA12. From the proband, they cloned a 2.5-kb genomic clone that contained a repeat of 93 uninterrupted CAGs. The CAG tract lies 133 nucleotides upstream of the reported transcription start site of the PPP2R2B gene, encoding a brain-specific regulatory subunit of the protein phosphatase PP2A. The PPP2R2B gene had been mapped to 5q31-q33 between markers D5S436 and D5S470. The region surrounding the CAG tract showed no homology with any additional genes in the EST database. Although the possibility that the CAG tract may lie within an unidentified gene overlapping or adjacent to PPP2R2B could not be excluded, an antibody probe did not detect polyglutamine expansions in protein derived from lymphoblastoid cell lines of affected family members. The correlation between repeat expansion and disease in pedigree R, the lack of expansions in controls, and the known capacity of expansion mutations outside of protein-coding regions to cause disease indicated that the expansion was causative. Although the precise role of the subunit encoded by PPP2R2B remained to be determined, the trimeric holoenzyme PP2A had been implicated in a number of cellular functions (Millward et al., 1999), including modulation of cell cycle progression (Mayer-Jaekel et al., 1993), tau phosphorylation (Sontag et al., 1999), and apoptosis (Deng et al., 1998; Santoro et al., 1998).
In a large pedigree, 'R,' of German descent with SCA12 (604326) described by Schols et al. (1997), Holmes et al. (1999) used repeat expansion detection (RED) to identify an expanded CAG repeat in the 5-prime region of the PPP2R2B gene in the proband and other affected family members. From the proband, they cloned a 2.5-kb genomic clone that contained a repeat of 93 uninterrupted CAGs. All 10 affected family members still living had a repeat expansion. They also tested 8 unaffected offspring of affected family members, 5 older than age 60 years and 3 aged 42 to 49 years. Seven lacked an expansion and a 49-year-old, with no signs or symptoms of SCA12, had an expansion. There was no apparent correlation between repeat size and age of onset, although the range of expanded alleles was relatively narrow (66 to 78 repeats) and the precise age of onset of tremor, typically the first symptom, was difficult to define in this disorder.
In a screening of 145 families with autosomal dominant cerebellar ataxia, Fujigasaki et al. (2001) identified a family from India with the CAG repeat expansion in the PPP2R2B gene.
Among 20 families from northern India with SCA12, Bahl et al. (2005) identified expanded CAG repeats ranging from 51 to 69 triplets. Unaffected individuals had repeats ranging from 8 to 23 triplets. Of note, 1 asymptomatic individual was homozygous for an expanded repeat (52 and 59 triplets). Haplotype analysis identified 1 haplotype that was associated with the disease alleles, indicating a common founder. Bahl et al. (2005) estimated that SCA12 accounts for about 16% of all ADCA cases in northern India.
In in vitro studies, Lin et al. (2010) demonstrated that expanded CAG repeats in the 5-prime region of the PPP2R2B gene caused increased gene expression.
Bahl, S., Virdi, K., Mittal, U., Sachdeva, M. P., Kalla, A. K., Holmes, S. E., O'Hearn, E., Margolis, R. L., Jain, S., Srivastava, A. K., Mukerji, M. Evidence of a common founder for SCA12 in the Indian population. Ann. Hum. Genet. 69: 528-534, 2005. [PubMed: 16138911] [Full Text: https://doi.org/10.1046/j.1529-8817.2005.00173.x]
Deng, X., Ito, T., Carr, B., Mumby, M., May, W. S., Jr. Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A. J. Biol. Chem. 273: 34157-34163, 1998. [PubMed: 9852076] [Full Text: https://doi.org/10.1074/jbc.273.51.34157]
Fujigasaki, H., Verma, I. C., Camuzat, A., Margolis, R. L., Zander, C., Lebre, A.-S., Jamot, L., Saxena, R., Anand, I., Holmes, S. E., Ross, C. A., Durr, A., Brice, A. SCA12 is a rare locus for autosomal dominant cerebellar ataxia: a study of an Indian family. Ann. Neurol. 49: 117-121, 2001. [PubMed: 11198281]
Holmes, S. E., O'Hearn, E. E., McInnis, M. G., Gorelick-Feldman, D. A., Kleiderlein, J. J., Callahan, C., Kwak, N. G., Ingersoll-Ashworth, R. G., Sherr, M., Sumner, A. J., Sharp, A. H., Ananth, U., Seltzer, W. K., Boss, M. A., Vieria-Saecker, A.-M., Epplen, J. T., Riess, O., Ross, C. A., Margolis, R. L. Expansion of a novel CAG trinucleotide repeat in the 5-prime region of PPP2R2B is associated with SCA12. (Letter) Nature Genet. 23: 391-392, 1999. [PubMed: 10581021] [Full Text: https://doi.org/10.1038/70493]
Lin, C.-H., Chen, C.-M., Hou, Y.-T., Wu, Y.-R., Hsieh-Li, H.-M., Su, M.-T., Lee-Chen, G.-J. The CAG repeat in SCA12 functions as a cis element to up-regulate PPP2R2B expression. Hum. Genet. 128: 205-212, 2010. [PubMed: 20533062] [Full Text: https://doi.org/10.1007/s00439-010-0843-2]
Mayer, R. E., Hendrix, P., Cron, P., Matthies, R., Stone, S. R., Goris, J., Merlevede, W., Hofsteenge, J., Hemmings, B. A. Structure of the 55-kDa regulatory subunit of protein phosphatase 2A: evidence for a neuronal-specific isoform. Biochemistry 30: 3589-3597, 1991. [PubMed: 1849734] [Full Text: https://doi.org/10.1021/bi00229a001]
Mayer-Jaekel, R. E., Ohkura, H., Gomes, R., Sunkel, C. E., Baumgartner, S., Hemmings, B. A., Glover, D. M. The 55 kd regulatory subunit of Drosophila protein phosphatase 2A is required for anaphase. Cell 72: 621-633, 1993. [PubMed: 8382567] [Full Text: https://doi.org/10.1016/0092-8674(93)90080-a]
Millward, T. A., Zolnierowicz, S., Hemmings, B. A. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem. Sci. 24: 186-191, 1999. [PubMed: 10322434] [Full Text: https://doi.org/10.1016/s0968-0004(99)01375-4]
Santoro, M. F., Annand, R. R., Robertson, M. M., Peng, Y.-W., Brady, M. J., Mankovich, J. A., Hackett, M. C., Ghayur, T., Walter, G., Wong, W. W., Giegel, D. A. Regulation of protein phosphatase 2A activity by caspase-3 during apoptosis. J. Biol. Chem. 273: 13119-13128, 1998. [PubMed: 9582351] [Full Text: https://doi.org/10.1074/jbc.273.21.13119]
Schalling, M., Hudson, T. J., Buetow, K. H., Housman, D. E. Direct detection of novel expanded trinucleotide repeats in the human genome. Nature Genet. 4: 135-139, 1993. [PubMed: 8348150] [Full Text: https://doi.org/10.1038/ng0693-135]
Schols, L., Amoiridis, G., Buttner, T., Przuntek, H., Epplen, J. T., Riess, O. Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann. Neurol. 42: 924-932, 1997. [PubMed: 9403486] [Full Text: https://doi.org/10.1002/ana.410420615]
Sontag, E., Nunbhakdi-Craig, V., Lee, G., Brandt, R., Kamibayashi, C., Kuret, J., White, C. L., III, Mumby, M. C., Bloom, G. S. Molecular interactions among protein phosphatase 2A, tau, and microtubules. J. Biol. Chem. 274: 25490-25498, 1999. [PubMed: 10464280] [Full Text: https://doi.org/10.1074/jbc.274.36.25490]