Role of the Nuclear Pore Component RANBP2 in Inflammatory Responses to Viral Infections

NCT06731790 | Completed

• 1 other identifier: RECHMPL23_0455
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this controlled, pathophysiological, exploratory interventional study is to compare the inflammatory phenotype of circulating immune cells, basal and following stimulation, from Acute Necrotizing Encephalopathy Type 1 (ANE1) patients with those from sex- and age-matched donors who do not carry the mutation.To date, no study has investigated the molecular mechanisms regulating the inflammatory response in ANE1 disease directly on patient samples. The primary endpoint in individuals in the "mutated RANBP2" arm is an inflammatory phenotype (hyperinflammatory monocytes, secretion of pro-inflammatory cytokines, anti-glycoprotein autoantibodies), significantly exacerbated basal and/or post-stimulation production of pro-inflammatory cytokines compared with the control arm. The secondary objective is to examine the allelic expression of mutant RANBP2 and characterize genetic variants by whole-exome sequencing, in order to associate them with RANBP2 protein localization and ANE crisis severity The researchers will compare the group of ANE1 patients with age- and sex-matched control groups, divided into two subgroups: unrelated controls and controls with familial ties. The aim is to study the different types of inflammatory responses and correlate them with the localization of the RANBP2 protein and the severity of ANE episodes. Participants will participate in a single visit during which demographic data, clinical history and a blood test will be collected with one (unrelated control) or two blood tubes (ANE1 and related control).

Conditions

Acute Necrotizing Encephalopathy; Rare Genetic Disease

Keywords

RANBP2; nuclear pore

Outcome Measures

Primary Outcomes (1)

• Comparison of the inflammatory phenotype of circulating immune cells, both basal and following stimulation, from ANE1 patients with those from sex- and age-matched donors not carrying the mutation

  These experiments will be carried out on blood, serum, peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages and microglia (MDM and MMG, respectively). The primary endpoint for individuals in the "mutated RANBP2" arm is an inflammatory phenotype, basal and/or after stimulation, that is significantly exacerbated compared with the "control" arms. Samples will be analyzed by ELISA/Luminex and flow cytometry. The expected difference will be a 2 to 10-fold upregulation in one or several markers of hyperinflammatory monocytes, and/or in one or several secreted pro-inflammatory cytokines, and/or in one or several autoantibodies, based on our results in PBMC treated with RANBP2-targeted RNA interference

  Baseline

Secondary Outcomes (3)

• Determination of the allelic expression of mutated RANBP2

  Baseline

• Determination of the effect of the T585M heterozygous mutation on RANBP2 localization

  Baseline

• Characterization of genetic variants that are significantly associated with ANE seizure severity

  Baseline

Study Arms (2)

Mutant RANBP2 associated with predisposition to ANE1

EXPERIMENTAL

Subjects aged 1 to 90 with a T585M mutation in RANBP2 for the "RANBP2 mutation" arm. During a single visit, 2 tubes of blood will be sampled, demographic data and clinical history collected, and a clinical examination performed.

Other: Blood sampling for inflammatory phenotype analysis; Genetic: Blood sampling for genetic analysis

Healthy control subjects

ACTIVE COMPARATOR

For healthy control subjects related to a person from the "mutant RANBP2" arm: During a single visit, 2 tubes of blood will be sampled, demographic data and clinical history collected, and a clinical examination performed. Healthy control subjects related to a person from the "mutant RANBP2" arm will be included in the third Secondary Outcome (whole exome sequencing). For healthy control subjects unrelated to a person from the "mutant RANBP2" arm: During a routine epilepsy consultation for children, or a family disease screening for adults, an additional blood tube will be sampled, demographic data collected and a clinical examination performed. Healthy control subjects unrelated to a person from the "mutant RANBP2" arm will not be included in the third Secondary Outcome (whole exome sequencing).

Other: Blood sampling for inflammatory phenotype analysis; Genetic: Blood sampling for genetic analysis

Interventions

Blood sampling for inflammatory phenotype analysis OTHER

Blood sampling for basal and post-stimulation inflammatory phenotype analysis

Healthy control subjects; Mutant RANBP2 associated with predisposition to ANE1

Blood sampling for genetic analysis GENETIC

Collection of a blood tube for whole exome sequencing, , long-read sequencing of the RANBP2 gene and analysis of the presence of the mutation by RTqPCR.

Healthy control subjects; Mutant RANBP2 associated with predisposition to ANE1

Eligibility Criteria

• Age: 1 Year - 90 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Obtaining written consent from adult participants
• Obtaining written consent from legal guardians of minors with their assent
• Subjects aged 1 to 90
• Subject with a T585M mutation in RANBP2 for the RANBP2 mutation arm.
• Subjects matched on age (+/- 10 years) and gender for the "control" arm.

You may not qualify if:

• Patient not affiliated to a social security scheme or not a beneficiary of such a scheme. (for example, a European Health Insurance Card (EHIC))
• Absence of written informed consent
• Person unable to give consent
• legally protected adult (guardianship, curatorship)
• Person deprived of liberty

Sponsors & Collaborators

• University Hospital, Montpellier: lead
• Institut de Recherche en Infectiologie de Montpellier (CNRS): collaborator
• A*STAR Infectious Diseases Labs: collaborator

Study Sites (1)

CHU Gui de Chauliac

Montpellier, Hérault, 34295, France

Location

Related Publications (15)

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• Okumura A, Mizuguchi M, Kidokoro H, Tanaka M, Abe S, Hosoya M, Aiba H, Maegaki Y, Yamamoto H, Tanabe T, Noda E, Imataka G, Kurahashi H. Outcome of acute necrotizing encephalopathy in relation to treatment with corticosteroids and gammaglobulin. Brain Dev. 2009 Mar;31(3):221-7. doi: 10.1016/j.braindev.2008.03.005. Epub 2008 May 5.

  PMID: 18456443 BACKGROUND

• Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev. 1997 Mar;19(2):81-92. doi: 10.1016/s0387-7604(96)00063-0.

  PMID: 9105653 BACKGROUND

• Lim HY, Ho VP, Lim TC, Thomas T, Chan DW. Serial outcomes in acute necrotising encephalopathy of childhood: A medium and long term study. Brain Dev. 2016 Nov;38(10):928-936. doi: 10.1016/j.braindev.2016.05.002. Epub 2016 May 30.

  PMID: 27256511 BACKGROUND

• Lee JH, Kim AJ, Kyong TY, Jang JH, Park J, Lee JH, Lee MJ, Kim JS, Suh YJ, Kwon SR, Kim CW. Evaluating the Outcome of Multi-Morbid Patients Cared for by Hospitalists: a Report of Integrated Medical Model in Korea. J Korean Med Sci. 2019 Jul 1;34(25):e179. doi: 10.3346/jkms.2019.34.e179.

  PMID: 31243937 BACKGROUND

• Sell K, Storch K, Hahn G, Lee-Kirsch MA, Ramantani G, Jackson S, Neilson D, von der Hagen M, Hehr U, Smitka M. Variable clinical course in acute necrotizing encephalopathy and identification of a novel RANBP2 mutation. Brain Dev. 2016 Sep;38(8):777-80. doi: 10.1016/j.braindev.2016.02.007. Epub 2016 Feb 26.

  PMID: 26923722 BACKGROUND

• Li J, Huo F, Wang S, Fan Y, Wu J, Zhang Z, Liu S, Wang Q. Recurrent infection triggered encephalopathy syndrome in a pediatric patient with RANBP2 mutation and severe acute respiratory syndrome coronavirus 2 infection. Pediatr Investig. 2023 Nov 19;7(4):290-296. doi: 10.1002/ped4.12406. eCollection 2023 Dec.

  PMID: 38050538 BACKGROUND

• Jiang J, Wang YE, Palazzo AF, Shen Q. Roles of Nucleoporin RanBP2/Nup358 in Acute Necrotizing Encephalopathy Type 1 (ANE1) and Viral Infection. Int J Mol Sci. 2022 Mar 24;23(7):3548. doi: 10.3390/ijms23073548.

  PMID: 35408907 BACKGROUND

• Levine JM, Ahsan N, Ho E, Santoro JD. Genetic Acute Necrotizing Encephalopathy Associated with RANBP2: Clinical and Therapeutic Implications in Pediatrics. Mult Scler Relat Disord. 2020 Aug;43:102194. doi: 10.1016/j.msard.2020.102194. Epub 2020 May 15.

  PMID: 32426208 BACKGROUND

• Denier C, Balu L, Husson B, Nasser G, Burglen L, Rodriguez D, Labauge P, Chevret L. Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene. J Neurol Sci. 2014 Oct 15;345(1-2):236-8. doi: 10.1016/j.jns.2014.07.025. Epub 2014 Jul 18.

  PMID: 25128471 BACKGROUND

• Neilson DE, Adams MD, Orr CM, Schelling DK, Eiben RM, Kerr DS, Anderson J, Bassuk AG, Bye AM, Childs AM, Clarke A, Crow YJ, Di Rocco M, Dohna-Schwake C, Dueckers G, Fasano AE, Gika AD, Gionnis D, Gorman MP, Grattan-Smith PJ, Hackenberg A, Kuster A, Lentschig MG, Lopez-Laso E, Marco EJ, Mastroyianni S, Perrier J, Schmitt-Mechelke T, Servidei S, Skardoutsou A, Uldall P, van der Knaap MS, Goglin KC, Tefft DL, Aubin C, de Jager P, Hafler D, Warman ML. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am J Hum Genet. 2009 Jan;84(1):44-51. doi: 10.1016/j.ajhg.2008.12.009.

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• Mizuguchi M, Abe J, Mikkaichi K, Noma S, Yoshida K, Yamanaka T, Kamoshita S. Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brain lesions. J Neurol Neurosurg Psychiatry. 1995 May;58(5):555-61. doi: 10.1136/jnnp.58.5.555.

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• Desgraupes S, Etienne L, Arhel NJ. RANBP2 evolution and human disease. FEBS Lett. 2023 Oct;597(20):2519-2533. doi: 10.1002/1873-3468.14749. Epub 2023 Oct 15.

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MeSH Terms

Conditions

Leukoencephalitis, Acute Hemorrhagic

Interventions

Blood Specimen Collection; Genetic Testing

Condition Hierarchy (Ancestors)

Encephalomyelitis, Acute Disseminated; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Leukoencephalopathies; Brain Diseases; Central Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques; Genetic Techniques; Genetic Services; Health Services; Health Care Facilities Workforce and Services; Diagnostic Services; Preventive Health Services

Study Officials

• Pierre MEYER, MD

  Montpellier University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Controlled, pathophysiological, exploratory interventional pilot study

Study Record Dates

• First Submitted: December 9, 2024
• First Posted: December 12, 2024
• Study Start: April 24, 2025
• Primary Completion: September 1, 2025
• Study Completion: September 1, 2025
• Last Updated: February 5, 2026

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share

Locations

FR (1)