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Clinical Infectious Diseases : An... Aug 2023
Topics: Male; Humans; Wiskott-Aldrich Syndrome; Skin; Face
PubMed: 37607355
DOI: 10.1093/cid/ciac955 -
Proceedings of the National Academy of... Aug 2023Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence...
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence of a specific cause, making its clinical management challenging. A better understanding of the molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies. We report that overexpression of (), here identified in a 38-y-old woman suffering from long-standing fatigue and exercise intolerance, can disrupt mitochondrial respiratory supercomplex formation and is associated with endoplasmic reticulum (ER) stress. Increased expression of in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. WASF3 induction by ER stress using endotoxin, well known to be associated with fatigue in humans, also decreased skeletal muscle complex IV levels in mice, while decreasing WASF3 levels by pharmacologic inhibition of ER stress improved mitochondrial function in the cells of the patient with chronic fatigue. Expanding on our findings, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels and aberrant ER stress activation. In addition to revealing a potential mechanism for the bioenergetic deficiency in ME/CFS, our study may also provide insights into other disorders associated with fatigue such as rheumatic diseases and long COVID.
Topics: Animals; Female; Humans; Mice; COVID-19; Fatigue Syndrome, Chronic; Mitochondria; Post-Acute COVID-19 Syndrome; Respiration; Wiskott-Aldrich Syndrome Protein Family; Mice, Transgenic
PubMed: 37579159
DOI: 10.1073/pnas.2302738120 -
Allergy, Asthma, and Clinical... Aug 2023Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene that leads to increased susceptibility to infections,...
Myelin oligodendrocyte glycoprotein antibody-associated disease as a novel presentation of central nervous system autoimmunity in a pediatric patient with Wiskott-Aldrich syndrome.
BACKGROUND
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene that leads to increased susceptibility to infections, thrombocytopenia, eczema, malignancies, and autoimmunity. Central nervous system (CNS) autoimmune manifestations are uncommon.
CASE PRESENTATION
We describe the case of a five-year-old boy with refractory thrombocytopenia and iron deficiency anemia who developed relapsing bilateral optic neuritis. Myelin oligodendrocyte glycoprotein antibody (MOG-IgG) via serum fluorescence-activated cell sorting assay was positive (titer 1:100), confirming a diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). At age six, molecular panel testing for genes associated with primary immunodeficiency identified a missense WAS gene variant. He was subsequently found to have decreased WAS protein expression, consistent with a diagnosis of WAS.
CONCLUSIONS
This case expands the reported spectrum of CNS autoimmunity associated with WAS and may help to inform long-term therapeutic options.
PubMed: 37550789
DOI: 10.1186/s13223-023-00827-x -
BioRxiv : the Preprint Server For... Jul 2023The mechanosensitive PIEZO channel family has been linked to over 26 disorders and diseases. Although progress has been made in understanding these channels at the...
The mechanosensitive PIEZO channel family has been linked to over 26 disorders and diseases. Although progress has been made in understanding these channels at the structural and functional levels, the underlying mechanisms of PIEZO-associated diseases remain elusive. In this study, we engineered four PIEZO-based disease models using CRISPR/Cas9 gene editing. We performed an unbiased chemical mutagen-based genetic suppressor screen to identify putative suppressors of a conserved gain-of-function variant that in human causes distal arthrogryposis type 5 (DA5; p. R2718P). Electrophysiological analyses indicate that is a gain-of-function allele. Using genomic mapping and whole genome sequencing approaches, we identified a candidate suppressor allele in the gene This gene is an ortholog of human (NCK-associated protein 1), a subunit of the Wiskott-Aldrich syndrome protein (WASP)-verprolin homologous protein (WAVE/SCAR) complex, which regulates F-actin polymerization. Depletion of by RNAi, or with the suppressor allele , significantly restored the small brood size and low ovulation rate, as well as alleviated the crushed oocyte phenotype of the mutant. Auxin-inducible degradation of GEX-3 revealed that only somatic-specific degradation of GEX-3 restored the reduced brood size in the mutants. Additionally, actin organization and orientation were disrupted and distorted in the mutants. Mutation of partially alleviated these defects. The identification of as a suppressor of the pathogenic variant suggests that the cytoskeleton plays an important role in regulating PIEZO channel activity and provides insight into the molecular mechanisms of DA5 and other PIEZO-associated diseases.
PubMed: 37546771
DOI: 10.1101/2023.07.24.550416 -
Blood Oct 2023Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid...
Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplantation for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase 1/2 clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral vector expressing the human WAS complementary DNA under the control of a 1.6-kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All patients were alive and well with sustained multilineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections, and bleeding diathesis was universal. Immune function was consistently improved despite subphysiologic levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity after GT, despite similar percentages of WAS protein-expressing cells and gene marking to those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), interleukin-10-producing regulatory B cells (Bregs), and transitional B cells. Thus, recovery of the Breg compartment, along with Tregs appears to be protective against development of autoimmunity after GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered at clinicaltrials.gov as #NCT01410825.
Topics: Humans; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; Hematopoietic Stem Cells; Hematopoietic Stem Cell Transplantation; Genetic Therapy; Eczema
PubMed: 37478401
DOI: 10.1182/blood.2022019117 -
Archivos Argentinos de Pediatria Feb 2024Wiskott-Aldrich syndrome (WAS) is an X-linked genetic disorder caused by mutations in the gene that encodes the Wiskott-Aldrich syndrome protein (WASp). Here, we report...
Wiskott-Aldrich syndrome (WAS) is an X-linked genetic disorder caused by mutations in the gene that encodes the Wiskott-Aldrich syndrome protein (WASp). Here, we report the clinical case of an 18-month-old boy diagnosed with Wiskott-Aldrich syndrome, who did not have an HLA-matched related or unrelated donor and was treated successfully with a hematopoietic stem cell transplant (HSCT) from a haploidentical family donor. Graft-versus-host disease (GvHD) prophylaxis included post-transplant cyclophosphamide (PT-Cy). At day +30, the peripheral blood-nucleated cell chimerism was 100% and the WAS protein had a normal expression. Currently, at month 32 post-transplant, the patient has hematological and immune reconstitution and complete donor chimerism without evidence of GvHD. HSCT with PT-Cy was a feasible and safe option for this patient with WAS, in which an HLA matched donor was not available.
Topics: Male; Child; Humans; Infant; Bone Marrow Transplantation; Wiskott-Aldrich Syndrome; Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Graft vs Host Disease
PubMed: 37471507
DOI: 10.5546/aap.2023-10061.eng -
Pediatric Dermatology 2024Treatment of severe eczema in patients with primary immunodeficiencies can be particularly challenging as there are no guidelines with regards to these conditions....
Treatment of severe eczema in patients with primary immunodeficiencies can be particularly challenging as there are no guidelines with regards to these conditions. Dupilumab is an interleukin (IL)-4Rα antagonist that inhibits both IL-4 and IL-13 and is approved for the treatment of atopic dermatitis in pediatric patients. In this report, we describe a patient with a case of severe eczema in the context of Wiskott-Aldrich syndrome-related disorder, who was successfully treated with dupilumab.
Topics: Humans; Child; Wiskott-Aldrich Syndrome; Antibodies, Monoclonal, Humanized; Dermatitis, Atopic; Eczema; Treatment Outcome; Severity of Illness Index
PubMed: 37469225
DOI: 10.1111/pde.15397 -
Diagnostics (Basel, Switzerland) Jun 2023The exact etiopathogenesis of Kawasaki disease (KD), the most common childhood vasculitis, remains unknown; however, an aberrant immune response, possibly triggered by... (Review)
Review
The exact etiopathogenesis of Kawasaki disease (KD), the most common childhood vasculitis, remains unknown; however, an aberrant immune response, possibly triggered by an infectious or environmental agent in genetically predisposed children, is believed to be the underlying pathogenetic mechanism. Patients with inborn errors of immunity (IEI) are predisposed to infections that trigger immune dysregulation due to an imbalance in various arms of the immune system. KD may develop as a complication in both primary and secondary immunodeficiencies. KD may occur either at disease presentation or have a later onset in IEIs. These include X-linked agammaglobulinemia (XLA), selective IgA deficiency, transient hypogammaglobulinemia of infancy; Wiskott-Aldrich syndrome (WAS), hyper IgE syndrome (HIES); chronic granulomatous disease (CGD), innate and intrinsic immunity defects, and autoinflammatory diseases, including PFAPA. Hitherto, the association between KD and IEI is confined to specific case reports and case series and, thus, requires extensive research for a comprehensive understanding of the underlying pathophysiological mechanisms. IEIs may serve as excellent disease models that would open new insights into the disease pathogenesis of children affected with KD. The current review highlights this critical association between KD and IEI supported by published literature.
PubMed: 37443545
DOI: 10.3390/diagnostics13132151 -
Biochemical and Biophysical Research... Sep 2023Strumpellin/Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complex subunit 5 (WASHC5) is a core component of the WASH complex, and its mutations confer...
Strumpellin/Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complex subunit 5 (WASHC5) is a core component of the WASH complex, and its mutations confer pathogenicity for hereditary spastic paraplegia (HSP) type SPG8, a rare neurodegenerative gait disorder. WASH complex activates actin-related protein-2/3-mediated actin polymerization and plays a pivotal role in intracellular membrane trafficking in endosomes. In this study, we examined the role of strumpellin in the regulation of structural plasticity of cortical neurons involved in gait coordination. Administration of a lentivirus containing a strumpellin-targeting short hairpin RNA (shRNA) to cortical motor neurons lead to abnormal motor coordination in mice. Strumpellin knockdown using shRNA attenuated dendritic arborization and synapse formation in cultured cortical neurons, and this effect was rescued by wild-type strumpellin expression. Compared with the wild-type, strumpellin mutants N471D or V626F identified in patients with SPG8 exhibited no differences in rescuing the defects. Moreover, the number of F-actin clusters in neuronal dendrites was decreased by strumpellin knockdown and rescued by strumpellin expression. In conclusion, our results indicate that strumpellin regulates the structural plasticity of cortical neurons via actin polymerization.
Topics: Animals; Mice; Actins; Endosomes; Gait; Neurons; RNA, Small Interfering; Spastic Paraplegia, Hereditary
PubMed: 37392480
DOI: 10.1016/j.bbrc.2023.06.071