A window-based analysis of common and low-frequency genetic variation from 2,836 ASD trios from the MSSNG cohort with the summary statistics of the population-based meta-analysis from the iPSYCH project using KnockoffHybrid-Z, a statistical method for the analysis of trio and population data in genome-wide association studies, in Yang et al., 2024, identified PTPRD as a significant loci with a false discovery rate (FDR) at 0.1 (ATAC p-value 6.43E-07). Association of PTPRD with ASD had previously been shown in an East Asian case-control association study (Liu et al., 2016). A number of de novo variants in PTPRD, including a de novo loss-of-function variant and a missense variant with a REVEL score greater than 0.5, have been identified in ASD probands (Yuen et al., 2017; Zhou et al., 2022). A PTPRD missense variant was found to be shared by both ASD-affected siblings in a Spanish multiplex family in Toma et al., 2014. A maternally-inherited deletion affecting the PTPRD gene was reported in a male patient presenting with autism spectrum disorder, intellectual disability, and sleep disturbance in Servetti et al., 2021. Copy number variation affecting the PTPRD gene has also been observed in individuals with ADHD (Elia et al., 2010) and OCD (Gazzellone et al., 2016). A genome-wide association analysis (GWAS) of obsessive-compulsive (OC) traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community in Burton et al., 2021 found that an intronic SNP in PTPRD (rs7856850) was significantly associated with OC traits at the genome-wide significance level (p-value 2.48E-08); this polymorphism was also associated with OCD in a meta-analysis of OCD case/control genome-wide datasets (p = 0.0069). Association of this gene with restless leg syndrome has also been reported in a case-control association study (Schormair et al., 2008).
Molecular Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular region, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus represents a receptor-type PTP. The extracellular region of this protein is composed of three Ig-like and eight fibronectin type III-like domains. Studies of the similar genes in chicken and fly suggest the role of this PTP is in promoting neurite growth, and regulating neurons axon guidance. The protein encoded by the PTPRD gene can bidirectionally induce pre- and post-synaptic differentiation of neurons by mediating interaction with IL1RAP and IL1RAPL1 trans-synaptically. Loss of PTPRD was found to increase the number of neurogenic transit-amplifying intermediate progenitor cells and cort
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
KnockoffHybrid: A knockoff framework for hybrid analysis of trio and population designs in genome-wide association studies
Loss of protein tyrosine phosphatase receptor delta PTPRD increases the number of cortical neurons, impairs synaptic function and induces autistic-like behaviors in adult mice
PTPRD heterozygous and homozygous null mice are viable and both models exhibit ASD-associated behaviors, including decreased sociability and social memory, and increased repetitive behaviors. These mice do not exhibit spatial learning and memory, hyperactivity or anxiety phenotypes. Both models show an increase in both excitatory and inhibitory neurons in the prefrontal and somatosensory cortices, and the homozygous knockout also shows increases in excitatory and inhibitory synaptic transmission in the prefrontal cortex.
References
Type
Title
Author, Year
Primary
Loss of protein tyrosine phosphatase receptor delta PTPRD increases the number of cortical neurons, impairs synaptic function and induces autistic-like behaviors in adult mice
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The Ptprd knockout allele (MGI:4458607) was built using a L1L2_Bact_P cassette inserted upstream of the critical exon. A LoxP site was inserted downstream of the critical exon. The critical exon is thus flanked by loxP sites. Sequential expression of flp and Cre recombinases results in a knockout allele.
Allele Type: Knockout
Strain of Origin: C57BL/6N-A^tm1Brd
Genetic Background: ES Cell Line: JM8A3.N1
Mutant ES Cell Line: Model Source: Wellcome Trust Sanger Institute
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The Ptprd knockout allele (MGI:4458607) was built using a L1L2_Bact_P cassette inserted upstream of the critical exon. A LoxP site was inserted downstream of the critical exon. The critical exon is thus flanked by loxP sites. Sequential expression of flp and Cre recombinases results in a knockout allele.
Allele Type: Knockout
Strain of Origin: C57BL/6N-A^tm1Brd
Genetic Background: ES Cell Line: JM8A3.N1
Mutant ES Cell Line: Model Source: Wellcome Trust Sanger Institute
Description: Knockout mice show an increase in parvalbumin-positive and somatostatin-positive neurons in the medial prefrontal and somatosensory cortices.
Exp Paradigm: Parvalbumin, Somatostatin, prefrontal cortex, somatosensory cortex
Description: Knockout mice show an increase in Tbr1-positive neurons in the medial prefrontal cortex and the somatosensory cortex, and an increase in Satb2-positive neurons in the somatosensory cortex.
Exp Paradigm: Tbr1, Satb2, prefrontal cortex, somatosensory cortex
Description: Heterozygous mice show an increase in somatostatin-positive neurons in the medial prefrontal and somatosensory cortices.
Exp Paradigm: Parvalbumin, Somatostatin, prefrontal cortex, somatosensory cortex
Description: Heterozygous mice show an increase in Tbr1-positive and Satb2-positive neurons in the somatosensory cortex.
Exp Paradigm: Tbr1, Satb2, prefrontal cortex, somatosensory cortex
