Alternative titles; symbols
HGNC Approved Gene Symbol: PTPA
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38): 9:129,110,950-129,148,946 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.11 | Parkinson disease 25, autosomal recessive early-onset, with impaired intellectual development | 620482 | Autosomal recessive | 3 |
PPP2R4, or PTPA, encodes a specific phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A; see 176915) (Van Hoof et al., 1995).
The core component of PP2A consists of a catalytic (C) subunit (e.g., PPP2CA; 176915) and a scaffold protein (A) subunit (e.g., PPP2R1A; 605983). Using purified recombinant proteins, Chao et al. (2006) found that PTPA and PP2A A-C dimers constituted a composite ATPase, and the interaction was independent of ATP or magnesium ion. The inclusion of PTPA altered the substrate specificity of PP2A, with enhanced phosphotyrosine phosphatase activity and decreased phosphoserine phosphatase activity.
Chao et al. (2006) reported the 1.9-angstrom crystal structure of human PTPA, which revealed a fold consisting of a core, a lid, and an extended linker joining the core and lid. Structural analysis uncovered a highly conserved surface patch bordering these 3 subdomains, as well as an associated deep pocket between the core and linker subdomains. Further analysis showed that the surface patch binds the PP2A A-C dimer, and the deep pocket binds ATP.
Van Hoof et al. (1995) demonstrated that human PTPA is encoded by a single-copy gene composed of 10 exons and 9 introns with a total length of about 60 kb. The 5-prime flanking sequence of the transcription start site was analyzed for its potential as a promoter. This region lacks a TATA sequence in the appropriate position relative to the transcription start. However, this region is very GC-rich and contains 4 Sp1 sites (SP1; 189906) upstream of the transcription start site, a feature common to many TATA-less promoters. Based on homology with DNA-binding consensus sequences of transcription factors, Van Hoof et al. (1995) identified several additional putative transcription factor binding sites in the promoter region. Transfection experiments with a construct containing the PTPA promoter region inserted 5-prime of a luciferase reporter gene demonstrated that the 5-prime flanking sequence of the PTPA gene indeed has promoter activity that seems to be cell-line dependent.
By fluorescence in situ hybridization, Van Hoof et al. (1995) mapped the PTPA gene to 9q34. Fluorescence in situ analysis of metaphase chromosomes of patients bearing the Philadelphia chromosome indicated that PTPA is positioned centromeric of ABL1 (189980) and probably is not involved in chronic myeloid leukemia.
In 4 patients from 2 families with autosomal recessive early-onset Parkinson disease-25 with impaired intellectual development (PARK25; 620482), Fevga et al. (2023) identified homozygous missense mutations in the PTPA gene (600756.0001-600756.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the families. In functional studies, both mutations showed decreased PTPA RNA stability and decreased protein levels. Expression of each mutation was associated with abnormal activation of PP2A phosphatase, which is involved in a number of signaling pathways and functions, including regulation of important proteins involved in neurodegeneration.
Fevga et al. (2023) found that knockdown of ptpa in Drosophila neurons resulted in impaired locomotion in the climbing test, which was age-dependent and reversible with L-DOPA treatment.
In 2 sibs, born to nonconsanguineous South African parents (family 1), with autosomal recessive early-onset Parkinson disease and impaired intellectual development (PARK25; 620482), Fevga et al. (2023) identified homozygosity for a c.893T-G transversion (c.893T-G, NM_178001) in the PTPA gene, resulting in a met298-to-arg (M298R) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family. The variant was not present in population databases, including gnomAD (v2.1.1).
In 2 sibs, born to consanguineous Libyan parents (family 2), with autosomal recessive early-onset Parkinson disease and impaired intellectual development (PARK25; 620482), Fevga et al. (2023) identified homozygosity for a c.512C-A transversion (c.512C-A, NM_178001) in the PTPA gene, resulting in an ala171-to-asp (A171D) substitution at a highly conserved residue. A first-cousin of the sibs had a similar phenotype but was not tested for the mutation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family. The variant was not present in the gnomAD database (v2.1.1).
Chao, Y., Xing, Y., Chen, Y., Xu, Y., Lin, Z., Li, Z., Jeffrey, P. D., Stock, J. B., Shi, Y. Structure and mechanism of the phosphotyrosyl phosphatase activator. Molec. Cell 23: 535-546, 2006. [PubMed: 16916641] [Full Text: https://doi.org/10.1016/j.molcel.2006.07.027]
Fevga, C., Tesson, C., Carreras Mascaro, A., Courtin, T., van Coller, R., Sakka, S., Ferraro, F., Farhat, N., Bardien, S., Damak, M., Carr, J., Ferrien, M., and 16 others. PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability. Brain 146: 1496-1510, 2023. [PubMed: 36073231] [Full Text: https://doi.org/10.1093/brain/awac326]
McCright, B., Rivers, A. M., Audlin, S., Virshup, D. M. The B56 family of protein phosphatase 2A (PP2A) regulatory subunits encodes differentiation-induced phosphoproteins that target PP2A to both nucleus and cytoplasm. J. Biol. Chem. 271: 22081-22089, 1996. [PubMed: 8703017] [Full Text: https://doi.org/10.1074/jbc.271.36.22081]
Van Hoof, C., Aly, M. S., Garcia, A., Cayla, X., Cassiman, J. J., Merlevede, W., Goris, J. Structure and chromosomal localization of the human gene of the phosphotyrosyl phosphatase activator (PTPA) of protein phosphatase 2A. Genomics 28: 261-272, 1995. [PubMed: 8530035] [Full Text: https://doi.org/10.1006/geno.1995.1140]