Intellectual disability
Gene: PTPA

PTPA (protein phosphatase 2 phosphatase activator)
EnsemblGeneIds (GRCh38): ENSG00000119383
EnsemblGeneIds (GRCh37): ENSG00000119383
OMIM: 600756, Gene2Phenotype
PTPA is in 1 panel

2 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

I don't know

Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are two unrelated cases with intellectual disability and hence this gene should be rated amber.
Created: 7 Jul 2023, 7:32 p.m. | Last Modified: 7 Jul 2023, 7:32 p.m.

Panel Version: 5.204

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual disability, MONDO:0001071

Publications

36073231

Created: 7 Jul 2023, 7:29 p.m.
Last Modified: 7 Jul 2023, 7:29 p.m.
Panel version: 5.200

Konstantinos Varvagiannis (Other)

I don't know

Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below.

There is currently no associated phenotype in OMIM, G2P, PanelApp Australia or SysNDD.

Consider inclusion in relevant panels (ID, Parkinsonism/movement disorders, etc) with amber rating pending further reports.

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Fevga, Tesson et al (2022 - PMID: 36073231) describe the features of 4 individuals, from 2 unrelated families, with biallelic pathogenic PTPA variants.

These presented with normal or delayed early milestones, learning disability and ID (mild to moderate) followed by progressive signs of parkinsonism (at the age of 11 yrs in 2 sibs, 15 yrs in another individual). Motor symptoms were responsive to levodopa and later to deep brain stimulation.

Linkage analysis in one consanguineous family followed by exome revealed homozygosity for a missense PTPA variant (NM_178001:c.893T>G/p.Met298Arg). Exome sequencing in affected subjects from the 2nd family revealed homozygosity for a further missense variant (c.512C>A/p.Ala171Asp). There were no other candidate variants for the phenotype following parental / segregation studies.

Role of the gene:
As the authors discuss, PTPA (or PPP2R4) is ubiquitously expressed in all tissues incl. brain and encodes a phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A). PP2A in turn, is the major Ser/Thr phosphatase in brain targeting a large number of proteins involved in diverse functions. Activation of PP2A is dependent on its methylation, which is negatively regulated by the PP2A-specific methylesterase (PME-1). By binding to PME-1, PTPA counteracts the negative influence of the former on PP2A. Pathogenic variants in genes encoding subunits/regulators of the PP2A complex (e.g. PPP2R1A or PPP2CA) are associated with neurodevelopmental disorders.

Variant studies:
Upon overexpression of wt and both variants in a HEK-293 cell line the authors demonstrated that both variants resulted in significantly reduced mRNA and protein levels (which for Ala171Asp were attributed to increased proteasomal degradation). Both variants were shown to result in impaired PP2A complex activation compared to wt.

Drosophila / animal models:
Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment.
Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice.
Sources: Literature
Created: 17 Sep 2022, 9:26 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual disability; Parkinsonism

Publications

36073231

Created: 17 Sep 2022, 9:26 a.m.

Panel version: 3.1720

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Amber

Phenotypes

Intellectual disability, MONDO:0001071

OMIM

600756

Clinvar variants

Variants in PTPA

Penetrance

Complete

Publications

36073231

Panels with this gene

Intellectual disability