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PPP2R5D
protein phosphatase 2 regulatory subunit B'delta
The PPP2R5D gene provides instructions for the B56-delta protein, a crucial regulatory subunit of the protein phosphatase 2A (PP2A) enzyme, predominantly active in the brain. The PPP2R5D gene encodes the B56-delta protein, a regulatory subunit for the protein phosphatase 2A (PP2A) enzyme.
PPP2R5D is located on the short (p) arm of chromosome 6, at band 6p21.1. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 6 in the library →Overview
The PPP2R5D gene, or protein phosphatase 2 regulatory subunit B'delta, plays a critical role in cellular regulation. It provides the genetic blueprint for a protein known as B56-delta, which is an essential component of the protein phosphatase 2A (PP2A) enzyme.
This enzyme complex is involved in dephosphorylation, a process that removes phosphate groups from proteins. Dephosphorylation is fundamental for controlling protein activity, influencing various cellular processes, including cell growth and gene regulation. The B56-delta subunit specifically directs PP2A to target particular proteins, thereby governing the enzyme's function.
What the gene does
The PPP2R5D gene directs the synthesis of the B56-delta protein, which functions as a B subunit within the protein phosphatase 2A (PP2A) enzyme complex. The primary role of PP2A is dephosphorylation, where it removes phosphate groups from other proteins. This biochemical modification is crucial for modulating protein activity, effectively switching them on or off.
The B56-delta subunit is pivotal because it dictates the specificity of the PP2A enzyme, determining which proteins become dephosphorylated and regulating the overall enzymatic activity. PP2A enzymes containing the B56-delta protein are predominantly found in the brain. Here, they are thought to regulate signalling pathways that are integral to the normal development and operational capacity of nerve cells, known as neurons.
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Chromosome location
The PPP2R5D gene is situated on chromosome 6, specifically at band 6p21.1. This precise location on the short arm of chromosome 6 helps define its genomic context.
Protein structure
The B56-delta protein, encoded by the PPP2R5D gene, consists of 602 amino acids. Its structural features include a disordered region spanning amino acids 1-96, which contains eight approximate tandem repeats of Q-P within amino acids 37-52. Specifically, individual repeat motifs are found at amino acids 37-38 (1), 39-40 (2), 41-42 (3), 43-44 (4), 45-46 (5), 47-48 (6; approximate), 49-50 (7; approximate), and 51-52 (8). Additionally, the protein features a class I SH3-binding motif at amino acids 523-530 and a nuclear localisation signal between amino acids 548-565.
Key variants
Variants within the PPP2R5D gene can lead to alterations in the B56-delta protein, impacting its ability to regulate the PP2A enzyme. These genetic changes can range from single amino acid substitutions to other types of pathogenic variants, all of which may disrupt the normal function of the protein. The clinical consequences of such variants are typically inherited in an autosomal dominant manner.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1258G>A | p.Glu420Lys | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.589G>A | p.Glu197Lys | Pathogenic/Likely pathogenic | ★★☆☆ | PPP2R5D-related disorder |
c.592G>A | p.Glu198Lys | Pathogenic | ★★☆☆ | Houge-Janssens syndrome 1 |
c.598G>A | p.Glu200Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Houge-Janssens syndrome 1 |
c.602C>G | p.Pro201Arg | Pathogenic | ★★☆☆ | Houge-Janssens syndrome 1 |
c.619T>A | p.Trp207Arg | Pathogenic | ★★☆☆ | Houge-Janssens syndrome 1 |
c.619T>C | p.Trp207Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Genetic developmental and epileptic encephalopathy |
c.621G>C | p.Trp207Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Houge-Janssens syndrome 1 |
c.621G>T | p.Trp207Cys | Pathogenic | ★★☆☆ | not provided |
c.625C>T | p.His209Tyr | Pathogenic/Likely pathogenic | ★★☆☆ | Houge-Janssens syndrome 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the PPP2R5D gene are associated with intellectual disability, often presenting with moderate to severe severity. Individuals may also experience weak muscle tone, medically termed hypotonia, and delayed development in speech and walking. These conditions are collectively referred to as PPP2R5D-related intellectual disability.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PPP2R5D variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the PPP2R5D gene is recognised on several NHS Genomic Medicine Service national test directories, indicating its clinical significance. It is listed on the DDG2P panel, and specific panels for Dystonia, chorea or related movement disorder (adult onset), Foetal anomalies (R21), Hydrocephalus (R86), and Intellectual disability.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the PPP2R5D gene?
The PPP2R5D gene provides instructions for making the B56-delta protein, which is a regulatory component of the PP2A enzyme. This enzyme removes phosphate groups from other proteins, influencing their activity and controlling various cellular processes, particularly in the brain.
What health conditions are associated with variants in the PPP2R5D gene?
Variants in the PPP2R5D gene are associated with PPP2R5D-related intellectual disability, which can manifest as moderate to severe intellectual disability, weak muscle tone (hypotonia), and delays in speech and walking development.
How is PPP2R5D-related intellectual disability inherited?
PPP2R5D-related intellectual disability is typically inherited in an autosomal dominant manner, meaning only one altered copy of the gene in each cell is sufficient to cause the condition.
References
- Shang L, Henderson LB, Cho MT. De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism. Neurogenetics. 2016. PMID: 26576547
- Loveday C, Tatton-Brown K, Clarke M. Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth. Human molecular genetics. 2015. PMID: 25972378
- Yu UY, Yoo BC, Ahn JH. Regulatory B Subunits of Protein Phosphatase 2A Are Involved in Site-specific Regulation of Tau Protein Phosphorylation. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology. 2014. PMID: 24757378
- Janssens V, Goris J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. The Biochemical journal. 2001. PMID: 11171037