PTPN21/Pez Is a Novel and Evolutionarily Conserved Key Regulator of Inflammation In Vivo

Campbell, Jennie S.; Davidson, Andrew J.; Todd, Henry Alfred; Rodrigues, Frederico S.L.M.; Elliot, Abigail; Early, Jason J; Lyons, David A.; Feng, Yi; Wood, Will

doi:10.1016/j.cub.2020.11.014

Cited by 7 publications

(9 citation statements)

References 36 publications

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“…An elder brother with mild learning disabilities but no seizures did not carry the variant. The variant is not present in the gnomAD database (v2 and v3) and has a CADD score of 29.7 30 , SIFT-score of 0.01, 33 and PolyPhen score of 0.936, 34 ) is an oncogenic protein known to be upregulated in several types of cancer cells 40 and functions as a key regulator of inflammation 41 . Two nonsynonymous single-nucleotide polymorphisms in PTPN21 showed association to schizophrenia in a GWAS study 42 .…”

Section: Genetic Diagnosismentioning

confidence: 99%

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De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies

Manivannan

Roovers

Smal

et al. 2021

Brain

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FZR1, which encodes the Cdh1 subunit of the Anaphase Promoting Complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Whole-exome sequencing in 39 patient-parent trios and subsequent targeted sequencing in an additional cohort of 211 patients was performed to identify novel genes involved in developmental and epileptic encephalopathy. Functional studies in Drosophila were performed using three different mutant alleles of the Drosophila homolog of FZR1 fzr. All three individuals carrying de novo variants in FZR1 had childhood onset generalized epilepsy, intellectual disability, mild ataxia and normal head circumference. Two individuals were diagnosed with the developmental and epileptic encephalopathy subtype Myoclonic Atonic Epilepsy. We provide genetic-association testing using two independent statistical tests to support FZR1 association with developmental epileptic encephalopathies. Further, we provide functional evidence that the missense variants are loss-of-function alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homolog fzr and overexpression studies, we show that patient variants can affect proper neurodevelopment. With the recent report of a patient with neonatal-onset with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and developmental epileptic encephalopathy, and expands the associated phenotype. We conclude that heterozygous loss-of-function of FZR1 leads to developmental epileptic encephalopathies associated with a spectrum of neonatal to childhood onset seizure types, developmental delay and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed myoclonic atonic epilepsy or developmental epileptic encephalopathy cases.

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Section: Genetic Diagnosismentioning

confidence: 99%

“…Christian Klambt) and Dp(1;3)DC472 P[acman] clone inserted in the third chromosome at the VK33 docking site [40][41][42] . To perform rescue experiments of fzr mutants, we subcloned the full length fzr cDNA from a pUASt-fzr vector 19 .…”

Section: Drosophila Fzr1 Allelesmentioning

confidence: 99%

De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies

Manivannan

Roovers

Smal

et al. 2021

Brain

View full text Add to dashboard Cite

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“…This multinucleotide variant is present twice heterozygous in gnomAD. PTPN21 (Tyrosine-protein phosphatase non-receptor type 21, MIM: 603271) is an oncogenic protein known to be upregulated in several types of cancer cells 50 and functions as a key regulator of inflammation 51 . Two non-synonymous single-nucleotide polymorphisms in PTPN21 showed association to schizophrenia in a GWAS study 52 .…”

Section: Resultsmentioning

confidence: 99%

De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies including Myoclonic Atonic Epilepsy

Manivannan

Roovers

Smal³

et al. 2021

Preprint

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FZR1, which encodes the Cdh1 subunit of the Anaphase Promoting Complex, plays an important role in neurodevelopment, both through the control of the cell cycle and through its multiple functions in post-mitotic neurons. In this study, the evaluation of 250 unrelated patients with developmental epileptic encephalopathies (DEE) and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Two variants led to the same amino acid change. All individuals had a DEE with childhood-onset generalized epilepsy, intellectual disability, mild ataxia, and normal head circumference. Two individuals were diagnosed with the DEE subtype Myoclonic Atonic Epilepsy (MAE). We provide gene burden testing using two independent statistical tests to support FZR1 association with DEE. Further, we provide functional evidence that the missense variants are loss-of-function (LOF) alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homolog fzr and overexpression studies, we show that patient variants do not support proper neurodevelopment. Along with a recent report of a patient with neonatal-onset DEE with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and DEE, and expands the associated phenotype. We conclude that heterozygous LOF of FZR1 leads to DEE associated with a spectrum of neonatal to childhood-onset seizure types, developmental delay, and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed MAE/DEE cases.

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“…PTPN21 has tyrosine phosphatase activity. 47 AQP4 is involved in the negative regulation of interleukin-1 beta and interleukin-6 production. 48 NR4A3 also plays a role in inflammation.…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity of inactivated rotavirus in rhesus monkey, and assessment of immunologic mechanisms

Zhou

et al. 2023

Human Vaccines & Immunotherapeutics

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Rotavirus is one of the main pathogens causing severe diarrhea in infants and young children < 5 years of age. The development of the next-generation rotavirus vaccine is of great significance for preventing rotavirus infection and reducing severe mortality. The current study aimed to develop and evaluate the immunogenicity of inactivated rotavirus vaccine (IRV) in rhesus monkeys. Monkeys received two or three IRV injections intramuscularly at a 4-week interval. Neutralizing antibodies, cellular immunity, PBMC gene expression profiling, and immune persistence were evaluated. Three-dose immunization of IRV induced a higher level of neutralizing, IgG and IgA antibodies compared to two-dose immunization. IRV induced IFN-γ secretion to mediate cellular immune responses, including robust pro-inflammatory and antiviral responses. Chemokine-mediated signaling pathways and immune response were broadly activated by IRV injection. The IRV-induced neutralizing antibodies resulting from two doses returned to baseline levels 20 weeks after full immunization, while those resulting from three doses returned to baseline levels 44 weeks after full immunization. Increasing immunization dose and injection number will help to improve IRV immunogenicity and neutralizing antibody persistence.

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PTPN21/Pez Is a Novel and Evolutionarily Conserved Key Regulator of Inflammation In Vivo

Cited by 7 publications

References 36 publications

De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies

De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies

De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies including Myoclonic Atonic Epilepsy

Immunogenicity of inactivated rotavirus in rhesus monkey, and assessment of immunologic mechanisms

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