| Title: |
Autoinflammatory encephalopathy due to PTPN1 haploinsufficiency: a case series |
| Authors: |
Zhu, Gaofeng; Didry-Barca, Blaise; Seabra, Luis; Rice, Gillian; Uggenti, Carolina; Touimy, Moncef; Rodero, Mathieu P; Trapero, Rolando Hernandez; Bondet, Vincent; Duffy, Darragh; Gautier, Philippe; Livingstone, Katie; Sutherland, Fraser; Lebon, Pierre; Parisot, Mélanie; Bole-Feysot, Christine; Masson, Cécile; Cagnard, Nicolas; Nitschké, Patrick; Anderson, Glenn; Assmann, Birgit; Barth, Magalie; Boespflug-Tanguy, Odile; d'Arco, Felice; Dorboz, Imen; Giese, Thomas; Hacohen, Yael; Hancarova, Miroslava; Husson, Marie; Lepine, Anne; Lim, Ming; Mancardi, Maria Margherita; Melki, Isabelle; Neubauer, David; Sa, Mario; Sedlacek, Zdenek; Seitz, Angelika; Rottman, Mika Shapiro; Sanquer, Sylvia; Straussberg, Rachel; Vlčková, Markéta; Villéga, Frédéric; Wagner, Matias; Zerem, Ayelet; Marsh, Joseph; Frémond, Marie-Louise; Kaliakatsos, Marios; Crow, Yanick; El-Daher, Marie-Thérèse; Lepelley, Alice |
| Contributors: |
The University of Edinburgh; Neurogénétique et neuroinflammation = Neurogenetics and neuroinflammation (Equipe Inserm U1163); Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); University of Manchester Manchester; Immunologie Translationnelle - Translational Immunology lab; Institut Pasteur Paris (IP)-Université Paris Cité (UPCité); Université Paris Cité (UPCité); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); Structure Fédérative de Recherche Necker (UAR 3633 / US24); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité); Great Ormond Street Hospital for Children London (GOSH); Universität Heidelberg Heidelberg = Heidelberg University; Centre Hospitalier Universitaire d'Angers (CHU Angers); Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)); AP-HP Hôpital universitaire Robert-Debré Paris; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); German Centre for Infection Research (DZIF); Heidelberg University Hospital Heidelberg; University College London UCL (UCL); Univerzita Karlova Praha, Česká republika = Charles University Prague, Czech Republic = Université Charles Prague, Republique tchèque (UK); University Hospital Motol Prague; CHU de Bordeaux Pellegrin Bordeaux; Hôpital de la Timone CHU - APHM (TIMONE); Guy's and St Thomas' NHS Foundation Trust; King‘s College London; IRCCS Istituto Giannina Gaslini Genoa, Italy; CHU Trousseau APHP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU); University Medical Centre Ljubljana (UMCL); Oxford University Hospitals NHS Trust; University of Oxford; Rambam Health Care Campus; Hôpital Necker - Enfants Malades AP-HP; Schneider Children’s Medical Center of Israel Petah Tikva; Tel Aviv University (TAU); Technische Universität Munchen = Technical University Munich = Université Technique de Munich (TUM); Helmholtz Zentrum München = German Research Center for Environmental Health (HMGU); Dr von Hauner Children's Hospital Munich, Germany; Ludwig Maximilian University Munich = Ludwig Maximilians Universität München (LMU); Tel Aviv Sourasky Medical Center Tel Aviv; Centre de Référence pour les Maladies Rhumatologiques Auto-Immunes et Systémiques CHU Necker (RAISE); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); YJC acknowledges the European Research Council (786142 E-T1IFNs), a UK Medical Research Council Human Genetics Unit core grant (MC_UU_00035/11), a state subsidy from the Agence Nationale de la Recherche (France) under the Investissements d’Avenir programme, bearing the reference ANR-10-IAHU-01, and funding from the Agence Nationale de la Recherche for the Phospho-IFN project (ANR-24-CE15-4638). GZ is funded by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 955576. MH, ZS, and MV acknowledge grant NU22-07-00165 from the Czech Ministry of Health.; ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010); ANR-24-CE15-4638,Phospho-IFN,Comprendre une nouvelle interféronopathie de type I due à des mutations de PTPN1(2024); European Project: 786142,ERC-2017-ADG,ERC-2017-ADG,E-T1IFNs(2018); European Project: 955576,H2020-MSCA-ITN-2020,H2020-MSCA-ITN-2020,INFLANET(2021) |
| Source: |
ISSN: 1474-4422. |
| Publisher Information: |
CCSD; Elsevier |
| Publication Year: |
2025 |
| Subject Terms: |
MESH: Humans; MESH: Male; MESH: Infant; MESH: Neuroinflammatory Diseases; MESH: Female; MESH: Haploinsufficiency; MESH: Child; MESH: Protein Tyrosine Phosphatase; Non-Receptor Type 1; Preschool; MESH: Adolescent; MESH: Brain Diseases; MESH: Mutation; [SDV]Life Sciences [q-bio] |
| Description: |
International audience ; BackgroundThrough the agnostic screening of patients with uncharacterised disease phenotypes for an upregulation of type I interferon (IFN) signalling, we identified a cohort of individuals heterozygous for mutations in PTPN1, encoding the protein-tyrosine phosphatase 1B (PTP1B). We aimed to describe the clinical phenotype and molecular and cellular pathology of this new disease.MethodsIn this case series, we identified patients and collected clinical and neuroradiological data through collaboration with paediatric neurology and clinical genetics colleagues across Europe (Czechia, France, Germany, Italy, Slovenia, and the UK) and Israel. Variants in PTPN1 were identified by exome and directed Sanger sequencing. The expression of IFN-stimulated genes was determined by quantitative (q) PCR or NanoString technology. Experiments to assess RNA and protein expression and to investigate type 1 IFN signalling were undertaken in patient fibroblasts, hTERT-immortalised BJ-5ta fibroblasts, and RPE-1 cells using CRISPR–Cas9 editing and standard cell biology techniques.FindingsBetween Dec 20, 2013, and Jan 11, 2023, we identified 12 patients from 11 families who were heterozygous for mutations in PTPN1. We found ten novel or very rare variants in PTPN1 (frequency on gnomAD version 4.1.0 of –6). Six variants were predicted as STOP mutations, two involved canonical splice-site nucleotides, and two were missense substitutions. In three patients, the variant occurred de novo, whereas in nine affected individuals, the variant was inherited from an asymptomatic parent. The clinical phenotype was characterised by the subacute onset (age range 1–8 years) of loss of motor and language skills in the absence of seizures after initially normal development, leading to spastic dystonia and bulbar involvement. Neuroimaging variably demonstrated cerebral atrophy (sometimes unilateral initially) or high T2 white matter signal. Neopterin in CSF was elevated in all ten patients who were tested, and ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/39986310; info:eu-repo/grantAgreement//786142/EU/Elaboration of the type I interferonopathies/E-T1IFNs; info:eu-repo/grantAgreement//955576/EU/Training European Experts in Inflammation: from the molecular players to animal models and the bedside/INFLANET; PUBMED: 39986310; PUBMEDCENTRAL: PMC7617446 |
| DOI: |
10.1016/S1474-4422(24)00526-X |
| Availability: |
https://pasteur.hal.science/pasteur-04989751; https://pasteur.hal.science/pasteur-04989751v1/document; https://pasteur.hal.science/pasteur-04989751v1/file/PIIS147444222400526X%281%29.pdf; https://doi.org/10.1016/S1474-4422(24)00526-X |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.19F2C526 |
| Database: |
BASE |