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Last update 08 May 2025

UNC13D

Last update 08 May 2025

Basic Info

Synonyms

Munc13-4, Protein unc-13 homolog D, unc-13 homolog D

+ [1]

Introduction

Plays a role in cytotoxic granule exocytosis in lymphocytes. Required for both granule maturation and granule docking and priming at the immunologic synapse. Regulates assembly of recycling and late endosomal structures, leading to the formation of an endosomal exocytic compartment that fuses with perforin-containing granules at the immunologic synapse and licences them for exocytosis. Regulates Ca(2+)-dependent secretory lysosome exocytosis in mast cells.

Drugs associated with UNC13D

MUNC-CD34

Target

UNC13D

Mechanism

UNC13D modulators

Active Org.

Assistance Publique des Hôpitaux de Paris SA

Originator Org.

Assistance Publique des Hôpitaux de Paris SA

Active Indication

Hemophagocytic Lymphohistiocytosis, Familial, 3

Inactive Indication-

Drug Highest PhasePhase 1/2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with UNC13D

NCT06736080

/ Not yet recruitingPhase 1/2IIT

A Phase I/II Open Label Non Randomized Study, Monocentric, Single Arm, Evaluating Safety and Efficacy of Gene Therapy of FHL 3 Caused by Mutations in the Human UNC13D Gene by Transplantation of a Single Dose of Autologous CD34+ Cells Transduced Ex Vivo with the UNC13D LV Vector Expressing the UNC13D CDNA

The investigators propose to replace HLA- partially compatible allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for FHL type 3 patients, with autologous transplantation of immunoselected gene-modified CD34+ cells, combined with transduced autologous T-cell each time this is possible and also to propose this alternative treatment as salvage in case of failure of a previous allogeneic HSCT. This approach should avoid the severe immunological complications (failure to engraft, acute or chronic graft versus host disease (GVHD)) and conditioning toxicities such as severe Veno-Occlusive Disease (VOD). As the clinical manifestations of FHL type 3 patients are triggered by opportunistic viral infections (often EBV) and can be poorly controlled or only transiently controlled by the available drugs , providing the patient after the conditioning with immediately functional autologous cytotoxic T-cells could be key to maintain the control of the viral infection and hopefully its eradication awaiting for the hematopoietic reconstitution . This procedure should avoid any reactivation of the viral infection and thus improving the patients' overall survival and event-free survival while clearing the ongoing triggering infections.

Start Date01 Jan 2025

Sponsor / Collaborator

Assistance Publique des Hôpitaux de Paris SA

100 Clinical Results associated with UNC13D

100 Translational Medicine associated with UNC13D

0 Patents (Medical) associated with UNC13D

323

Literatures (Medical) associated with UNC13D

08 Apr 2025·Blood Advances

The role of genetic sequencing in the diagnostic workup for chronic immune thrombocytopenia

Article

Author: Downes, Kate ; Cooper, Nichola ; Hart, Alice ; Ademokun, Christine ; Lango-Allen, Hana ; Simeoni, Ilenia ; Joshi, Nehal ; Paul, Deena ; Vladescu, Camelia

AbstractImmune thrombocytopenia (ITP) is a heterogenous autoimmune disorder diagnosed by excluding other conditions. Misdiagnosis of primary ITP occurs in patients with inherited thrombocytopenia and primary immunodeficiency syndromes. This study investigates whether genetic testing for inherited thrombocytopenia or primary immunodeficiency can enhance diagnostic accuracy in ITP, and guide treatment strategies. We performed whole genome sequencing or targeted panel sequencing on peripheral blood samples in a cohort of 80 participants with chronic ITP, utilizing the ThromboGenomics panel (n = 72) and the Genomics of Rare Immune Disorders panel (n = 50) consisting of genes known to cause bleeding and platelet disorders (BPDG) or primary immuodeficiency genes (PIDG) respectively. A replication cohort of 73 patients underwent clinical genomics testing with either the R90 (BPDG, n = 35) or R15 (PIDG, n = 50) National Health Service Genomics panels. Known pathogenic or likely pathogenic, disease-causing, variants were identified in 9 patients in the first cohort (11%, 95% confidence interval [CI]: 5-20); 7 patients (10%, 95% CI: 4-19) in BPDG and 2 patients (4% CI,1-14) in PIDG. In addition, 26 patients (32.5%) carried variants of uncertain significance. In the replication cohort, 8% (95% CI, 2-20) and 9% (95% CI, 2-23) of patients had a pathogenic variant identified on the R15 (PIDG) or R90 panel (BPDG), respectively. The findings impacted clinical management such as avoidance of immunosuppression (ANKRD26, GP1BB, ETV6, TUBB1, and ITGB3) and eligibility for allogeneic stem cell transplantation (UNC13D). Our findings demonstrate that genomic sequencing identifies diagnostically relevant variants in patients with chronic ITP. Identification of these variants can guide treatment decisions and improve patient outcomes.

01 Apr 2025·Clinical Rheumatology

Whole exome sequencing for identifying rare genetic variants related to idiopathic granulomatous mastitis

Article

Author: Ozer, Leyla ; Koksal, Hande

AbstractBackgroundsTo reveal rare genetic factors that cause susceptibility to idiopathic granulomatous mastitis (IGM).MethodsWhole exome sequencing (WES) was performed in 30 patients with histopathologically diagnosed idiopathic granulomatous mastitis. WES analysis mainly focused on 317 genes linked to autoimmunity, autoinflammation, and immune dysregulation.ResultsA total of 141 variants were detected in 100 genes. The 40% (12/30) of patients had pathogenic or likely pathogenic variants. The pathogenic/likely pathogenic variants were 10.6% of all variants, and the rest of the variants (89.4%) were classified as VUS. Most of the variants were heterozygous (97.2%) only 4 variants (2.8%) were homozygous. Pathogenic/likely pathogenic variants were detected in FCGR1A, MPO, F5, IL36RN, CLUH, C9, NAXD, PROC, THRB, IFI30, COQ2, RNASEH2B, and SLC29A3 genes. The highest number of variants were detected in UNC13D, VPS13B, EPHB4, NLRP12, TCIRG1, TOM1, IRF9, and PIK3CG.ConclusionUp to date, our study is the first whole exome sequencing study of IGM patients which aims to find out the rare variants related to etiopathogenesis of the disease. We identified 141 single nucleotide variants of 100 genes, and most of these variants were found in innate immunity-related genes. The current study provides clues for identifying the etiologic factors and designing further functional studies in this rare disease with unknown etiopathogenesis. Key Points•Autoimmunity/autoinflammation-related genetic factors are blamed for etiopathogenesis of idiopathic granulomatous mastitis (IGM).•Mutation in genes related to innate immunity, especially in macrophage functions and phagocytosis, may lead to IGM susceptibility.•Potential candidate genes for genetic susceptibility to IGM may shed light for new treatment options.

01 Nov 2024·Biochemical and Biophysical Research Communications

Dense but not alpha granules of platelets are required for insulin secretion from pancreatic β cells

Article

Author: Karwen, Till ; Stegner, David ; Sumara, Grzegorz ; Kolczyńska-Matysiak, Katarzyna ; Loeffler, Mona ; Kassouf, Toufic ; Hawro, Izabela

OBJECTIVESPlatelets, originally described for their role in blood coagulation, are now also recognized as key players in modulating inflammation, tissue regeneration, angiogenesis, and carcinogenesis. Recent evidence suggests that platelets also influence insulin secretion from pancreatic β cells. The multifaceted functions of platelets are mediated by the factors stored in their alpha granules (AGs) and dense granules (DGs). AGs primarily contain proteins, while DGs are rich in small molecules, and both types of granules are released during blood coagulation. Specific components stored in AGs and DGs are implicated in various inflammatory, regenerative, and tumorigenic processes. However, the relative contributions of AGs and DGs to the regulation of pancreatic β cell function have not been previously explored.METHODSIn this study, we utilized mouse models deficient in AG content (neurobeachin-like 2 (Nbeal2) -deficient mice) and models with defective DG release (Unc13d-deficiency in bone marrow-derived cells) to investigate the impact of platelet granules on insulin secretion from pancreatic β cells.RESULTSOur findings indicate that AG deficiency has little to no effect on pancreatic β cell function and glucose homeostasis. Conversely, mice with defective DG release exhibited glucose intolerance and reduced insulin secretion. Furthermore, Unc13d-deficiency in hematopoietic stem cells led to a reduction in adipose tissue gain in obese mice.CONCLUSIONSObtained data suggest that DGs, but not AGs, mediate the influence of platelets on pancreatic β cells, thereby modulating glucose metabolism.

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UNC13D

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