BACKGROUND: Through 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. METHODS: In 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. FINDINGS: Between 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 <1·25 × 10:sup>-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 all probands demonstrated an upregulation of IFN-stimulated genes in whole blood. Although clinical stabilisation and neuroradiological improvement was seen in both treated and untreated patients, in six of eight treated patients, high-dose corticosteroids were judged clinically to result in an improvement in neurological status. Of the four asymptomatic parents tested, IFN signalling in blood was normal (three patients) or minimally elevated (one patient). Analysis of patient blood and fibroblasts showed that tested PTPN1 variants led to reduced levels of PTPN1 mRNA and PTP1B protein, and in-vitro assays demonstrated that loss of PTP1B function was associated with impaired negative regulation of type 1 IFN signalling. INTERPRETATION: PTPN1 haploinsufficiency causes a type 1 IFN-driven autoinflammatory encephalopathy. Notably, some patients demonstrated stabilisation, and even recovery, of neurological function in the absence of treatment, whereas in others, the disease appeared to be responsive to immune suppression. Prospective studies are needed to investigate the safety and efficacy of specific immune suppression approaches in this disease population. FUNDING: The UK Medical Research Council, the European Research Council, and the Agence Nationale de la Recherche.

APHP Centre de Référence LEUKOFRANCE Service de Neuropediatrie Hopital Robert Debre Paris France; Universite Paris Cité NeuroDiderot UMR INSERM 1141 Hopital Robert Debre Paris France

Biochemistry Metabolomics and Proteomics Department Necker Hospital Assistance Publique Hôpitaux de Paris Centre Université Paris Cité Paris France

Bioinformatics Platform Institut Imagine Structure Fédérative de Recherche Necker INSERM U1163 et INSERM US24 CNRS UMS3633 Université Paris Cité Paris France

Department of Biology and Medical Genetics Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czechia

Department of Child Adolescent and Developmental Neurology University Children's Hospital Ljubljana Slovenia

Department of Diagnostic Imaging Rambam Health Care Campus Faculty of Medicine Technion Haifa Israel

Department of Histopathology Camelia Botnar Laboratories Great Ormond Street Hospital for Children London UK

Department of Neurology Great Ormond Street Hospital for Children London UK; Department of Neuroscience Institute of Child Health University College London London UK

Department of Neurology Great Ormond Street Hospital for Children London UK; Queen Square MS Centre UCL Queen Square Institute of Neurology Faculty of Brain Sciences University College London London UK

Department of Neuroradiology Heidelberg University Hospital Heidelberg Germany

Department of Paediatric Neurology Oxford University Hospitals NHS Foundation Trust Oxford UK

Department of Radiology Great Ormond Street Hospital for Children London UK

Division of Evolution and Genomic Sciences School of Biological Sciences Faculty of Biology Medicine and Health University of Manchester Manchester Academic Health Science Centre Manchester UK

Evelina London Children's Hospital Guy's and St Thomas' NHS Foundation Trust London UK; Department of Women and Children's Health School of Life Course Sciences King's College London London UK

Genomics Core Facility Institut Imagine Structure Fédérative de Recherche Necker INSERM U1163 et INSERM US24 CNRS UAR3633 Université Paris Cité Paris France

Heidelberg University Medical Faculty Heidelberg Centre for Paediatric and Adolescent Medicine Department 1 Division of Paediatric Neurology and Metabolic Medicine Heidelberg Germany

Institute of Human Genetics Klinikum Rechts der Isar School of Medicine Technical University of Munich Munich Germany; Institute for Neurogenomics Helmholtz Zentrum München Neuherberg Germany; Division of Paediatric Neurology Developmental Neurology and Social Pediatrics Dr von Hauner Children's Hospital Munich Germany

Institute of Immunology and German Centre for Infection Research Partner Site Heidelberg Heidelberg University Hospital Heidelberg Germany

Institute of Paediatric Neurology Schneider Children's Medical Centre of Israel Petach Tikva Israel; Faculty of Medical and Health Sciences Tel Aviv University Tel Aviv Israel

Laboratory of Neurogenetics and Neuroinflammation Imagine Institute INSERM UMR1163 Université Paris Cité Paris France

Laboratory of Neurogenetics and Neuroinflammation Imagine Institute INSERM UMR1163 Université Paris Cité Paris France; Department of General Paediatrics Armand Trousseau Hospital AP HP Sorbonne Université Paris France

Laboratory of Neurogenetics and Neuroinflammation Imagine Institute INSERM UMR1163 Université Paris Cité Paris France; Pediatric Neurology Institute Dana Dwek Children's Hospital; Reference Centre for Inflammatory Rheumatism Autoimmune Diseases and Systemic Interferonopathies in Children Paris France; Department of Paediatric Haematology Immunology and Rheumatology Necker Enfants Malades Hospital AP HP Paris France

Medical School Université Paris Cité Paris France

MRC Human Genetics Unit Institute of Genetics and Cancer University of Edinburgh Edinburgh UK

MRC Human Genetics Unit Institute of Genetics and Cancer University of Edinburgh Edinburgh UK; Laboratory of Neurogenetics and Neuroinflammation Imagine Institute INSERM UMR1163 Université Paris Cité Paris France

Service de Génétique Centre Hospitalier Universitaire d'Angers Angers France

Service de Neuropédiatrie Hôpital de la Timone Enfants Marseille France

Tel Aviv Sourasky Medical Center Faculty of Medicine Tel Aviv University Tel Aviv Israel

Translational Immunology Unit Institut Pasteur Université Paris Cité Paris France

Unit of Child Neuropsychiatry EpiCARE Network IRCCS Giannina Gaslini Genova Italy

Unité de Neurologie de l'Enfant et de l'Adolescent CHU Pellegrin Bordeaux France

Zobrazit více v PubMed

Tonks NK. Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol. 2006;7(11):833–46. PubMed

Stanford SM, Bottini N. Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders. Nat Rev Drug Discov. 2023;22(4):273–94. doi: 10.1038/s41573-022-00618-w. PubMed DOI PMC

Read NE, Wilson HM. Recent Developments in the Role of Protein Tyrosine Phosphatase 1B (PTP1B) as a Regulator of Immune Cell Signalling in Health and Disease. Int J Mol Sci. 2024;25(13) doi: 10.3390/ijms25137207. PubMed DOI PMC

Elchebly M, Payette P, Michaliszyn E, et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science. 1999;283(5407):1544–8. PubMed

Gunawardana J, Chan FC, Telenius A, et al. Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma. Nat Genet. 2014;46(4):329–35. PubMed

Lee MN, Roy M, Ong SE, et al. Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach. Nat Immunol. 2013;14(2):179–85. doi: 10.1038/ni.2509. PubMed DOI PMC

Myers MP, Andersen JN, Cheng A, et al. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J Biol Chem. 2001;276(51):47771–4. PubMed

Xia T, Yi XM, Wu X, Shang J, Shu HB. PTPN1/2-mediated dephosphorylation of MITA/STING promotes its 20S proteasomal degradation and attenuates innate antiviral response. Proc Natl Acad Sci U S A. 2019;116(40):20063–9. doi: 10.1073/pnas.1906431116. PubMed DOI PMC

Bourdeau A, Dube N, Tremblay ML. Cytoplasmic protein tyrosine phosphatases, regulation and function: the roles of PTP1B and TC-PTP. Curr Opin Cell Biol. 2005;17(2):203–9. PubMed

Parlato M, Nian Q, Charbit-Henrion F, et al. Loss-of-Function Mutation in PTPN2 Causes Aberrant Activation of JAK Signaling Via STAT and Very Early Onset Intestinal Inflammation. Gastroenterology. 2020;159(5):1968–71.:e4. PubMed

Awwad J, Souaid M, Yammine T, et al. A homozygous missense variant in PTPN2 with early-onset Crohn’s disease, growth failure and dysmorphic features in an infant: a case report. J Genet. 2023;102 PubMed

Thaventhiran JED, Lango Allen H, Burren OS, et al. Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature. 2020;583(7814):90–5. doi: 10.1038/s41586-020-2265-1. PubMed DOI PMC

Jeanpierre M, Cognard J, Tusseau M, et al. Haploinsufficiency in PTPN2 leads to early-onset systemic autoimmunity from Evans syndrome to lupus. J Exp Med. 2024;221(9) doi: 10.1084/jem.20232337. PubMed DOI PMC

Sa M, Hacohen Y, Alderson L, et al. Immunotherapy-responsive childhood neurodegeneration with systemic and central nervous system inflammation. Eur J Paediatr Neuro. 2018;22(5):882–8. PubMed

Rice GI, Forte GM, Szynkiewicz M, et al. Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. Lancet Neurol. 2013;12(12):1159–69. doi: 10.1016/S1474-4422(13)70258-8. PubMed DOI PMC

Lepelley A, Martin-Niclos MJ, Le Bihan M, et al. Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling. J Exp Med. 2020;217(11) doi: 10.1084/jem.20200600. PubMed DOI PMC

Rodero MP, Decalf J, Bondet V, et al. Detection of interferon alpha protein reveals differential levels and cellular sources in disease. J Exp Med. 2017;214(5):1547–55. doi: 10.1084/jem.20161451. PubMed DOI PMC

Lebon P, Badoual J, Ponsot G, Goutieres F, Hemeury-Cukier F, Aicardi J. Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J Neurol Sci. 1988;84(2–3):201–8. PubMed

Keedy DA, Hill ZB, Biel JT, et al. An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering. Elife. 2018;7 doi: 10.7554/eLife.36307. PubMed DOI PMC

Hjortness MK, Riccardi L, Hongdusit A, et al. Evolutionarily Conserved Allosteric Communication in Protein Tyrosine Phosphatases. Biochemistry. 2018;57(45):6443–51. PubMed

Kingdom R, Wright CF. Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts. Front Genet. 2022;13:920390. doi: 10.3389/fgene.2022.920390. PubMed DOI PMC

Gruber C, Bogunovic D. Incomplete penetrance in primary immunodeficiency: a skeleton in the closet. Hum Genet. 2020;139(6–7):745–57. doi: 10.1007/s00439-020-02131-9. PubMed DOI PMC

Rice GI, Park S, Gavazzi F, et al. Genetic and phenotypic spectrum associated with IFIH1 gain-of-function. Hum Mutat. 2020;41(4):837–49. doi: 10.1002/humu.23975. PubMed DOI PMC

Crow YJ, group AGS. Clinical Non-penetrance Associated with Biallelic Mutations in the RNase H2 Complex. J Clin Immunol. 2023;43(4):706–8. doi: 10.1007/s10875-023-01438-2. PubMed DOI PMC

Dale RC, Brilot F, Fagan E, Earl J. Cerebrospinal fluid neopterin in paediatric neurology: a marker of active central nervous system inflammation. Dev Med Child Neurol. 2009;51(4):317–23. PubMed

Han VX, Mohammad SS, Jones HF, et al. Cerebrospinal fluid neopterin as a biomarker of treatment response to Janus kinase inhibition in Aicardi-Goutieres syndrome. Dev Med Child Neurol. 2022;64(2):266–71. PubMed

Crow YJ, Casanova JL. Human life within a narrow range: The lethal ups and downs of type I interferons. Sci Immunol. 2024;9(97):eadm8185. PubMed

Orcesi S, Pessayno A, Biancheri R, et al. Aicardi-Goutieres syndrome presenting atypically as a sub-acute leukoencephalopathy. Eur J Paediatr Neuro. 2008;12(5):408–11. PubMed

D’Arrigo S, Riva D, Bulgheroni S, et al. Aicardi-Goutieres syndrome: description of a late onset case. Developmental Medicine and Child Neurology. 2008;50(8):631–4. PubMed

Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol. 1997;39(4):214–23. PubMed

Hidecker MJ, Paneth N, Rosenbaum PL, et al. Developing and validating the Communication Function Classification System for individuals with cerebral palsy. Dev Med Child Neurol. 2011;53(8):704–10. doi: 10.1111/j.1469-8749.2011.03996.x. PubMed DOI PMC