Alternative titles; symbolsPROTEIN PHOSPHATASE 2, 65-KD REGULATORY SUBUNIT A, ALPHAPR65-ALPHAHGNC Approved Gene Symbol: PPP2R1ACytogenetic location: 19q13.41 ...
Alternative titles; symbols
HGNC Approved Gene Symbol: PPP2R1A
Cytogenetic location: 19q13.41 Genomic coordinates (GRCh38): 19:52,190,051-52,229,517 (from NCBI)
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).
▼ Cloning and Expression
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.
▼ Gene Function
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.
▼ Biochemical Features
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.
▼ Gene Structure
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).
▼ Molecular Genetics
The Deciphering Developmental Disorders Study (2015) identified 3 patients with autosomal dominant mental retardation-36 (MRD36; 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 MRD36, 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.
▼ ALLELIC VARIANTS ( 3 Selected Examples):
.0001 MENTAL RETARDATION, AUTOSOMAL DOMINANT 36
In 2 unrelated girls with autosomal dominant mental retardation-36 (MRD36; 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.
.0002 MENTAL RETARDATION, AUTOSOMAL DOMINANT 36
In a girl with autosomal dominant mental retardation-36 (MRD36; 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.
.0003 MENTAL RETARDATION, AUTOSOMAL DOMINANT 36
In a patient with autosomal dominant mental retardation-36 (MRD36; 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.