HGNC Approved Gene Symbol: PPP2R5D
Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38): 6:42,984,570-43,012,342 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.1 | Houge-Janssens syndrome 1 | 616355 | Autosomal dominant | 3 |
The PPP2R5D gene encodes a B56 regulatory subunit of protein phosphatase-2A (PP2A), an intracellular serine/threonine phosphatase (summary by Houge et al., 2015).
For background information on PP2A and its subunits, see 601643.
McCright et al. (1996) cloned the B56-delta gene from a human fetal brain cDNA library using a partial cDNA sequence. They found that B56-delta encoded a 602-amino acid protein with a predicted molecular mass of 69,947 Da. This subunit is able to form a functional trimeric PP2A phosphatase when combined with an A and a C subunit.
Louis et al. (2011) found expression of the Ppp2r5d gene in various brain regions in the mouse: expression was highest in the striatum and thalamus, intermediate in the brainstem and hippocampus, and weak in the cortex and cerebellum.
McCright et al. (1996) observed that the location of B56-delta varies with the cell cycle, being present in both cytoplasm and nucleus in interphase cells but concentrated in the nucleus of mitotic and recently divided cells. Both B56-beta (601644) and B56-delta are highly expressed in the adult brain, and mRNA for these isoforms increases 3- to 5-fold when neuroblastoma cell lines are induced to differentiate by retinoic acid treatment.
McCright et al. (1996) mapped the gene for the delta subunit of protein phosphatase-2A, designated PPP2R5D, to chromosome 6p21.1 by fluorescence in situ hybridization.
The Deciphering Developmental Disorders Study (2015) identified 4 patients with autosomal dominant intellectual developmental disorder-35 (MRD35; 616355) who had heterozygous de novo missense mutations in the PPP2R5D gene. Three patients carried the same mutation (E198K; 601646.0001), and the fourth carried a different mutation (P201R; 601646.0002). The authors suggested that these mutations may perturb interactions between subunits of the protein phosphatase-2 complex.
In 7 unrelated patients with MRD35, Houge et al. (2015) identified 5 different de novo heterozygous missense mutations in the PPP2R5D gene (601646.0001-601646.0005). Three of the patients carried the same E198K mutation. The mutations were found by parent-child trio exome sequencing and confirmed by Sanger sequencing. All mutations clustered in a highly conserved acidic loop that faces the A and C subunits of the PP2A complex, except one (P53S; 601646.0003). In vitro functional expression studies in HEK293 cells showed that all mutations, except P53S, showed deficient holoenzyme formation of PP2A with decreased association of the mutant PPP2R5D subunit to the A or C subunits, consistent with a dominant-negative effect. Houge et al. (2015) suggested that disruption of normal phosphorylation in the brain may result in brain dysfunction, perhaps by having far-reaching consequences for regulation of localized signaling.
Loveday et al. (2015) identified 2 different heterozygous missense mutations in the PPP2R5D gene (601646.0001 and 601646.0004) in 3 unrelated patients with MRD35 associated with overgrowth, mainly macrocephaly. Functional studies of the variants were not performed, but Loveday et al. (2015) postulated that they could plausibly alter the ability of PP2A to dephosphorylate target substrates. The first 2 patients were ascertained from a larger cohort of 111 parent-child trios with overgrowth syndrome, often associated with intellectual disability, who underwent exome sequencing. The third patient was ascertained from a cohort of 152 individuals with overgrowth phenotypes for whom parental DNA was not available. Loveday et al. (2015) postulated that the mutations may disrupt the PI3K (see 171834)/AKT1 (164730) growth regulatory cascade.
Louis et al. (2011) found that Ppp2r5d-null mice developed a progressive increase in phosphorylated tau (MAPT; 157140) in the brainstem and spinal cord compared to wildtype mice. However, neurofibrillary tangles did not develop. These changes were associated with progressive sensorimotor deficits, but not cognitive dysfunction. Knockout mice also showed decreased phosphorylation and increased activity of GSK3-beta (GSK3B; 605004), as well as decreased CKD5 (123831) activity and absence of its activator p35 (CDK5R1; 603460). The findings implied that disruption of a proper kinase-phosphatase balance may underlie the tau neuropathology of these mutant mice.
In 3 unrelated patients with autosomal dominant intellectual developmental disorder-35 (MRD35; 616355), the Deciphering Developmental Disorders Study (2015) identified a heterozygous de novo missense mutation in the PPP2R5D gene, a G-to-A transition at chromosome coordinate g.42,975,003 (chr6.42,975,003G-A, GRCh37) resulting in a glu198-to-lys (E198K) substitution. No functional studies were performed.
Houge et al. (2015) identified a de novo heterozygous E198K mutation, resulting from a c.592G-A transition (c.592G-A, NM_006245.2), in 3 unrelated patients with MRD35. The mutation occurred in a highly conserved acidic loop that faces the A and C subunits of the PP2A complex. Overexpression of E198K in HEK293 cells resulted in increased phosphorylation of a PPP2R5D substrate, consistent with a dominant-negative effect. The patients with the E198K mutation had a more severe phenotype compared to patients with other PPP2R5D mutations, reflecting the greater impact of the mutation on binding to subunit A and C of the PP2A holocomplex demonstrated in in vitro cellular studies.
Loveday et al. (2015) identified a de novo heterozygous E198K mutation (c.592G-A, NM_006245) in a patient (COG1744) with MRD35 associated with overgrowth, including increased head circumference. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present among 1,000 population controls or in the ExAC browser. Functional studies of the variant were not performed, but the mutation occurred in the substrate specificity loop, and Loveday et al. (2015) postulated that it could plausibly alter the ability of PP2A to dephosphorylate target substrates.
In a patient with autosomal dominant intellectual developmental disorder-35 (MRD35; 616355), the Deciphering Developmental Disorders Study (2015) identified a heterozygous C-to-G transversion at chromosome coordinate g.42,975,013 (chr6.42,975,013C-G, GRCh37) in the PPP2R5D gene, resulting in a pro201-to-arg (P201R) substitution. This mutation occurred as a de novo event. No functional studies were performed.
Houge et al. (2015) identified a de novo heterozygous P201R mutation (c.602C-G, NM_006245.2) in a patient with MRD35.
In a patient with autosomal dominant intellectual developmental disorder-35 (MRD35; 616355), Houge et al. (2015) identified a de novo heterozygous c.157C-T transition (c.157C-T, NM_006245.2) in the PPP2R5D gene, resulting in a pro53-to-ser (P53S) substitution.
In 2 unrelated patients with autosomal dominant intellectual developmental disorder-35 (MRD35; 616355), Houge et al. (2015) identified a de novo heterozygous c.598G-A transition (c.598G-A, NM_006245.2) in the PPP2R5D gene, resulting in a glu200-to-lys (E200K) substitution in a highly conserved acidic loop that faces the A and C subunits of the PP2A complex.
Loveday et al. (2015) identified a heterozygous E200K mutation (c.598G-A, NM_006245) in 2 unrelated patients (COG1674 and COG0328) with MRD35 associated with overgrowth, mainly macrocephaly. The mutation in 1 of the patients was proven to have occurred de novo. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present among 1,000 population controls or in the ExAC browser. Functional studies of the variant were not performed, but the mutation occurred in the substrate specificity loop, and Loveday et al. (2015) postulated that it could plausibly alter the ability of PP2A to dephosphorylate target substrates.
In a patient with autosomal dominant intellectual developmental disorder-35 (MRD35; 616355), Houge et al. (2015) identified a de novo heterozygous c.619T-A transversion (c.619T-A, NM_006245.2) in the PPP2R5D gene, resulting in a trp207-to-arg (W207R) substitution in a highly conserved acidic loop that faces the A and C subunits of the PP2A complex.
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]
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]
Louis, J. V., Martens, E., Borghgraef, P., Lambrecht, C., Sents, W., Longin, S., Zwaenepoel, K., Pijnenborg, R., Landrieu, I., Lippens, G., Ledermann, B., Gotz, J., Van Leuven, F., Goris, J., Janssens, V. Mice lacking phosphatase PP2A subunit PR61/B'delta (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3-beta. Proc. Nat. Acad. Sci. 108: 6957-6962, 2011. [PubMed: 21482799] [Full Text: https://doi.org/10.1073/pnas.1018777108]
Loveday, C., Tatton-Brown, K., Clarke, M., Westwood, I., Renwick, A., Ramsay, E., Nemeth, A., Campbell, J., Joss, S., Gardner, M., Zachariou, A., Elliott, A., Ruark, E., van Montfort, R., Childhood Overgrowth Collaboration, Rahman, N. Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth. Hum. Molec. Genet. 24: 4775-4779, 2015. Note: Erratum: Hum. Molec. Genet. 28: 1578 only, 2019. [PubMed: 25972378] [Full Text: https://doi.org/10.1093/hmg/ddv182]
McCright, B., Brothman, A. R., Virshup, D. M. Assignment of human protein phosphatase 2A regulatory subunit genes B56-alpha, B56-beta, B56-gamma, B56-delta, and B56-epsilon (PPP2R5A--PPP2R5E), highly expressed in muscle and brain, to chromosome regions 1q41, 11q12, 3p21, 6p21.1, and 7p11.2-to-p12. Genomics 36: 168-170, 1996. [PubMed: 8812429] [Full Text: https://doi.org/10.1006/geno.1996.0438]
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]