PTPN4 germline variants result in aberrant neurodevelopment and growth

Abstract

Summary Protein-tyrosine phosphatases (PTPs) are pleomorphic regulators of eukaryotic cellular responses to extracellular signals that function by modulating the phosphotyrosine of specific proteins. A handful of PTPs have been implicated in germline and somatic human disease. Using exome sequencing, we identified missense and truncating variants in PTPN4 in six unrelated individuals with varying degrees of intellectual disability or developmental delay. The variants occurred de novo in all five subjects in whom segregation analysis was possible. Recurring features include postnatal growth deficiency or excess, seizures, and, less commonly, structural CNS, heart, or skeletal anomalies. PTPN4 is a widely expressed protein tyrosine phosphatase that regulates neuronal cell homeostasis by protecting neurons against apoptosis. We suggest that pathogenic variants in PTPN4 confer risk for growth and cognitive abnormalities in humans.

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

“…HOPE analyses indeed position the L72S structural change quite close to the shallow binding cleft located between the FERM subdomains ( Figure 2 ). Recently six additional mutations in PTPN4 were implicated to cause (neuro) developmental disorders ( Chmielewska et al, 2021 ); five are documented in dbSNP (rs1677776998; rs1678083679; rs1678390512; rs1679218434; rs1259252500) and one (c.2171T>C p.I724T) is not, but all are predicted to disrupt PTP-MEG1 function ( Chmielewska et al, 2021 ). Also in the ClinVar database PTPN4 SNPs rs1679434397 (c.2491C>A, p.L831I) and, once more, rs1679218434 (c.1738G>T, p.D580Y) have been connected to intellectual disability and autism spectrum disorder (ASD), but functional evidence is currently lacking.…”

Progress in the mechanism of neuronal surface P antigen modulating hippocampal function and implications for autoimmune brain disease

“…In the brain, PTPMEG/PTPN4 is not only mainly expressed in cerebellum and thalamus, but also in the cortex and hippocampus, distributing in neurons within the cytoplasm, axons, dendrites, dendritic spines and PSD [41,47 ▪▪ ,48]. PTPMEG/PTPN4 has been involved in neurodevelopmental disorders [47 ▪▪ ,48,49] and glutamatergic synaptic transmission and plasticity [27 ▪▪ ,41,50].…”

“…PTPMEG/PTPN4 is a large protein of 926 amino acids containing an N-terminal FERM (Band 4.1, Ezrin, Radixin and Moesin) domain that mediates interactions with the plasma membrane, a PDZ (PSD-95/Dlg/ZO-1) domain that interacts with PDZ-ligand domains present in certain glutamatergic receptors and a C-terminal catalytic tyrosine phosphatase domain [40–46]. In the brain, PTPMEG/PTPN4 is not only mainly expressed in cerebellum and thalamus, but also in the cortex and hippocampus, distributing in neurons within the cytoplasm, axons, dendrites, dendritic spines and PSD [41,47 ▪▪ ,48]. PTPMEG/PTPN4 has been involved in neurodevelopmental disorders [47 ▪▪ ,48,49] and glutamatergic synaptic transmission and plasticity [27 ▪▪ ,41,50].…”

“…The Rett syndrome is a neurodevelopmental disorder primarily caused by variants of the Mecp2 transcription factor, which includes PTPMEG/PTPN4 among its regulated proteins [49]. In addition, missense and truncated variants of PTPMEG/PTPN4 are described in seven unrelated individuals with varying degrees of intellectual disability, developmental delay, autistic features and structural CNS anomalies [47 ▪▪ ,48]. Three of these variants have mutations in the FERM domain and two of them prevent the localization of PTPMEG/PTPN4 to dendritic spines [47 ▪▪ ,48].…”

“…In addition, missense and truncated variants of PTPMEG/PTPN4 are described in seven unrelated individuals with varying degrees of intellectual disability, developmental delay, autistic features and structural CNS anomalies [47 ▪▪ ,48]. Three of these variants have mutations in the FERM domain and two of them prevent the localization of PTPMEG/PTPN4 to dendritic spines [47 ▪▪ ,48]. Knockout models reveal roles of PTPMEG/PTPN4 in axonal development in Drosophila [51] and motor learning and cerebellar glutamatergic synaptic plasticity in mice [46].…”