Li et al., 2023 reported three unrelated patients presenting with a neurodevelopmental disorder caused by PLPPR4 haploinsufficiency that was characterized by mild intellectual disability, language delay or disorder, motor delay, and autistic behavior (including a diagnosis of autism spectrum disorder in one patient); subsequent functional characterization of iPSC-derived neurons from a patient with a de novo heterozygous PLPPR4 deletion demonstrated reduced density of dendritic protrusions, shorter neurites, and reduced axon length. Additional de novo variants in this gene, including a de novo loss-of-function variant and two de novo missense variants, have been reported in ASD probands (Satterstrom et al., 2020; Zhou et al., 2022; Trost et al., 2022). PLPPR4 +/- mice were shown to display abnormal function in cortical networks, reduced resilience in stress-related behaviors, reduced social interaction, and a significant decrease in prepulse inhibition compared to wild-type mice in Vogt et al., 2015. Schneider et al., 2017 demonstrated that PLPPR4 -/- mice displayed increased ambulation, increased speed of locomotion, increased anxiety and stereotypic behaviors including rearing, leaning, and self-grooming.
Molecular Function
The protein encoded by this gene belongs to the lipid phosphate phosphatase (LPP) family. LPPs catalyze the dephosphorylation of a number of bioactive lipid mediators that regulate a variety of cell functions. This protein is specifically expressed in neurons. It is located in the membranes of outgrowing axons and has been shown to be important for axonal outgrowth during development and regenerative sprouting.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Molecular cause and functional impact of altered synaptic lipid signaling due to a prg-1 gene SNP.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Plppr4 gene was disrupted by inserting an IRES-LacZ-MC1-Neo cassette, which deletes the extracellular domains coded by exons 5 and 6 and blocks translation of the intracellular tail coded by exon 7. The last 119 bp of exon 4, entire exons 5 and 6 and the first 494 bp of exon 7 were replaced with a cassette containing the 5 end three stop codons in every frame followed by an internal ribosome entry site, the lacZ reporter coding sequence, an independent promoter (MC1)-controlled neomycin-resistance gene, and a polyadenylation sequence.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6
ES Cell Line: Not specified
Mutant ES Cell Line: E14-TG2a-derived embryonic stem (ES) cells
Model Source: Nitsch laboratory, Charite, Universitaetsmedizin Berlin (PMID 19766573)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Plppr4 gene was disrupted by inserting an IRES-LacZ-MC1-Neo cassette, which deletes the extracellular domains coded by exons 5 and 6 and blocks translation of the intracellular tail coded by exon 7. The last 119 bp of exon 4, entire exons 5 and 6 and the first 494 bp of exon 7 were replaced with a cassette containing the 5 end 3 stop codons in every frame followed by an internal ribosome entry site, the lacZ reporter coding sequence, an independent promoter (MC1)-controlled neomycin-resistance gene, and a polyadenylation sequence. Plppr4 heterozygous mice are an animal correlate for human monoallelic PRG-1-R345T carriers who only have one functional prg-1 allele.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6
ES Cell Line: Not specified
Mutant ES Cell Line: E14-TG2a-derived embryonic stem (ES) cells
Model Source: Nitsch laboratory, Charite, Universitaetsmedizin Berlin (PMID 19766573)
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mosaic Plppr4 KO mice with deletion of exons 4 to 6 in a subset of CA1 pyramidal neurons following in utero injection of cre recombinase, used for conducting single cell studies in cells with loss of of Plppr4. Authors have indicated in the study that Plppr4 is exclusively expressed in neurons, using ultrastructural studies to indicate that it is expressed in the postsynaptic structures of hippocampal glutamatergic neurons
Allele Type: Mosaic
Strain of Origin: Genetic Background: C57BL/6
ES Cell Line: Not specified
Mutant ES Cell Line: E14-TG2a-derived embryonic stem (ES) cells
Model Source: Nitsch laboratory, Charite, Universitaetsmedizin Berlin (PMID 19766573)
Description: Mutants display increased latency to fall off the accelerating rotarod and reach higher speeds before they fall compared to controls.
Exp Paradigm: NA
Miniature post synaptic current frequency: excitatory1
Increased
Description: Mutants exhibit increased mepsc frequency compared to controls.
Exp Paradigm: Glutamatergic currents at similar stimulation intensities and stimulation electrode positions were recorded
Description: Mutants show reduced uptake of fluorescence-labeled lipids (neuronsfluorescence-coupled phosphatidic acid) in neurons when compared to wildtype.
Exp Paradigm: NA
Description: Mutants were highly hyperexcitable compared to controls, detectable by increased fepsp slope.
Exp Paradigm: Extracellular field epsps evoked by schaffer collateral stimulation in the stratum radiatum of the ca1 hippocampal region were recorded.
Electroencephalogram (eeg): signature of seizure/epilepsy1
Increased
Description: Mutants exhibit hypersynchronized activity, preictal events, ictal events and tonic-clonic seizures, compared to controls. mutants exhibit interictal discharges and seizure-like events in gamma oscillation recordings of the hippocampal network compared to controls, following carbachol administration.
Exp Paradigm: In vivo electrographic recordings using intracranial, epidural electrodes above the somatosensory cortex; field potential shifts were recorded
Description: Mutants display increased leaning frequency and reduced rearing behavior compared to controls in the small open filed. mutants display decreased rearing and no change in leaning frequency compared to controls in the large open field.
Exp Paradigm: NA
Description: Mutants show absence of plppr4 protein in immunohistochemical analysis of the hippocampal ca1 region and in western blot analyses of whole brain homogenates, compared to controls. correct homologous recombination was confirmed in mutants.
Exp Paradigm: Southern blot
Description: Mutants show absence of plppr4 protein in immunohistochemical analysis of the hippocampal ca1 region and in western blot analyses of whole brain homogenates, compared to controls. correct homologous recombination was confirmed in mutants.
Exp Paradigm: Immunohistochemistry
Description: Mutants show absence of plppr4 protein in immunohistochemical analysis of the hippocampal ca1 region and in western blot analyses of whole brain homogenates, compared to controls. correct homologous recombination was confirmed in mutants.
Exp Paradigm: Western blot
Description: Plppr4 heterozygotes display increased amplitude of local field potentials in the whisker-specific cortical barrel in response to the second whisker stimulation, compared to controls, indicating a reduction in sensorimotor gating.
Exp Paradigm: Pre-attentive cortical information processing was measured by sensory gating in a double-pulse whisker stimulation model.
Description: Plppr4 heterozygotes display increase in number and duration of multiunit activity burst when compared to wildtype control mice, indicating a shift in excitatory/inhibitory balance toward excitation within cortical microcircuitries.
Exp Paradigm: NA
Description: Mutants were highly hyperexcitable compared to controls, detectable by increased fepsp slope.
Exp Paradigm: Extracellular field epsps evoked by schaffer collateral stimulation in the stratum radiatum of the ca1 hippocampal region were recorded.
Description: Mutants show correct homologous recombination in southern blot and pcr compared to controls.
Exp Paradigm: Polymerase chain reaction (pcr)
Miniature post synaptic current frequency: excitatory1
Increased
Description: Mutants show increase in frequency of stimulus evoked epscs compared to controls, indicating that increase in neuronal excitability is due to the lack of plppr4 at the postsynaptic side.
Exp Paradigm: Recordings from gfp+ (prg-1 cko genotype) and gfp- (wt genotype) ca1 pyramidal neurons were performed in acute hippocampal slices.
Miniature post synaptic current amplitude: excitatory1
Increased
Description: Mutants show increase in amplitudes of stimulus evoked epscs compared to controls.
Exp Paradigm: Recordings from gfp+ (prg-1 cko genotype) and gfp- (wt genotype) ca1 pyramidal neurons were performed in acute hippocampal slices. the majority of cells expressed prg-1, as did, consequently. majority of cells expressed plppr4 as did the majority of afferents on a mutant ca1 pyramidal cell derived from wildtype ca3 neurons.
