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International Journal of Genomics 2024Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive genetic disease characterized by clinical symptoms such as eczema, thrombocytopenia with small platelets,...
Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive genetic disease characterized by clinical symptoms such as eczema, thrombocytopenia with small platelets, immune deficiency, prone to autoimmune diseases, and malignant tumors. This disease is caused by mutations of the gene encoding WASprotein (WASP). The locus and type of mutations of the gene and the expression quantity of WASP were strongly correlated with the clinical manifestations of patients. We found a novel mutation in the gene (c.931 + 5G > C), which affected splicing to produce three abnormal mRNA, resulting in an abnormally truncated WASP. This mutation led to a reduction but not the elimination of the normal WASP population, resulting in causes X-linked thrombocytopenia (XLT) with mild clinical manifestations. Our findings revealed the pathogenic mechanism of this mutation.
PubMed: 38410787
DOI: 10.1155/2024/2277956 -
Proximity proteomics reveals role of Abelson interactor 1 in the regulation of TAK1/RIPK1 signaling.Molecular Oncology Nov 2023Dysregulation of the adaptor protein Abelson interactor 1 (ABI1) is linked to malignant transformation. To interrogate the role of ABI1 in cancer development, we mapped...
Dysregulation of the adaptor protein Abelson interactor 1 (ABI1) is linked to malignant transformation. To interrogate the role of ABI1 in cancer development, we mapped the ABI1 interactome using proximity-dependent labeling (PDL) with biotin followed by mass spectrometry. Using a novel PDL data filtering strategy, considering both peptide spectral matches and peak areas of detected peptides, we identified 212 ABI1 proximal interactors. These included WAVE2 complex components such as CYFIP1, NCKAP1, or WASF1, confirming the known role of ABI1 in the regulation of actin-polymerization-dependent processes. We also identified proteins associated with the TAK1-IKK pathway, including TAK1, TAB2, and RIPK1, denoting a newly identified function of ABI1 in TAK1-NF-κB inflammatory signaling. Functional assays using TNFα-stimulated, ABI1-overexpressing or ABI1-deficient cells showed effects on the TAK1-NF-kB pathway-dependent signaling to RIPK1, with ABI1-knockout cells being less susceptible to TNFα-induced, RIPK1-mediated, TAK1-dependent apoptosis. In sum, our PDL-based strategy enabled mapping of the ABI1 proximal interactome, thus revealing a previously unknown role of this adaptor protein in TAK1/RIPK1-based regulation of cell death and survival.
Topics: Humans; Tumor Necrosis Factor-alpha; Proteomics; Signal Transduction; NF-kappa B; Apoptosis; Receptor-Interacting Protein Serine-Threonine Kinases; Adaptor Proteins, Signal Transducing; Cytoskeletal Proteins; Wiskott-Aldrich Syndrome Protein Family
PubMed: 36635880
DOI: 10.1002/1878-0261.13374 -
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 -
Modulating Liquid-Liquid Phase Separation of Nck Adaptor Protein against Enteropathogenic Infection.ACS Central Science Dec 2023Signaling proteins often form biomolecular condensates through liquid-liquid phase separation (LLPS) during intracellular signal transduction. Modulating the LLPS...
Signaling proteins often form biomolecular condensates through liquid-liquid phase separation (LLPS) during intracellular signal transduction. Modulating the LLPS property of intracellular protein condensates will redirect intracellular signals and provide a potential way to regulate cellular physiology. Phosphorylation of multiple tyrosine residues of the transmembrane receptor nephrin is known to drive the LLPS of the adaptor protein Nck and neuronal Wiskott-Aldrich Syndrome protein (N-WASP) and form the Nck signaling complex. Phosphorylation of the translocated intimin receptor (Tir) in the host cell may recruit this enteropathogenic (EPEC) virulence factor to the Nck signaling complex and lead to the entry of EPEC into the intestine cell. In this work, we first identified a phosphotyrosine (pY)-containing peptide based on the sequence similarity of nephrin and Tir; promoted the LLPS of Nck and N-WASP, mimicking the role of phosphorylated nephrin. Next, we designed a covalent blocker of Nck, peptide based on the selected pY peptides, which site-selectively reacted with the SH2 domain of Nck (Nck-SH2) at Lys331 through a proximity-induced reaction. The covalent reaction of with Nck blocked the protein binding site of Nck-SH2 and disintegrated the /Nck/N-WASP condensates. In the presence of membrane-translocating peptide L17E, entered Caco-2 cells in the cytosol, reduced the number of Nck puncta, and rendered Caco-2 cells resistant to EPEC infection. Site-selective covalent blockage of Nck thereby disintegrates intracellular Nck condensates, inhibits actin reorganization, and shuts down the entrance pathway of EPEC. This work showcases the promotion or inhibition of protein phase separation by synthetic peptides and the use of reactive peptides as LLPS disruptors and signal modulators.
PubMed: 38161366
DOI: 10.1021/acscentsci.3c01068 -
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 -
Journal of Clinical Immunology Jul 2023There is a lack of data on post-HSCT non-osteopenic bone pathology specifically for children with inborn errors of immunity (IEI). We collected data on non-osteopenic...
PURPOSE
There is a lack of data on post-HSCT non-osteopenic bone pathology specifically for children with inborn errors of immunity (IEI). We collected data on non-osteopenic bone pathology in children with IEI post-HSCT over two decades in a large tertiary pediatric immunology center.
METHODS
Descriptive study with data analysis of bone pathology in allo-HSCT for IEI was performed between 1/1/2000 to 31/12/2018 including patients alive at follow-up to July 2022. Records were analyzed for bone pathology and risk factors. Exclusion criteria included isolated reduced bone density, fractures, and skeletal anomalies due to underlying IEI and short stature without other bone pathology. Bone pathologies were divided into 5 categories: bone tumors; skeletal dysplasia; avascular necrosis; evolving bone deformities; slipped upper femoral epiphysis.
RESULTS
A total of 429 children received HSCT between 2000 and 2018; 340 are alive at last assessment. Non-osteopenic bone pathology was observed post-HSCT in 9.4% of patients (32/340, mean 7.8 years post-HSCT). Eleven patients (34%) had > 1 category of bone pathology. Seventeen patients (17/32; 53%) presented with bilateral bone pathology. The majority of patients received treosulfan-based conditioning (26/32; 81.2%). Totally, 65.6% (21/32) of patients had a history of prolonged steroid use (> 6 months). Pain was the presenting symptom in 66% of patients, and surgical intervention was required in 43.7%. The highest incidence of bone pathologies was seen in Wiskott-Aldrich syndrome (WAS) (n = 8/34; 23.5%) followed by hemophagocytic lymphohistiocytosis patients (n = 3/16; 18.8%).
CONCLUSION
Non-osteopenic bone pathology in long-term survivors of allo-HSCT for IEI is not rare. Most patients did not present with complaints until at least 5 years post-HSCT highlighting the need for ongoing bone health assessment for patients with IEI. Children presenting with stunted growth and bone pathology post-HSCT should undergo skeletal survey to rule out development of post-HSCT skeletal dysplasia. Increased rates and complexity of bone pathology were seen amongst patients with Wiskott-Aldrich syndrome.
Topics: Child; Humans; Wiskott-Aldrich Syndrome; Hematopoietic Stem Cell Transplantation; Risk Factors; Lymphohistiocytosis, Hemophagocytic; Incidence; Retrospective Studies; Transplantation Conditioning
PubMed: 36930409
DOI: 10.1007/s10875-023-01465-z -
Molecular Therapy. Methods & Clinical... Jun 2024
PubMed: 38680553
DOI: 10.1016/j.omtm.2024.101247 -
Cancers Sep 2023Squamous cell carcinoma (SCC) is one of the most common forms of skin cancer in humans, and Neural Wiskott-Aldrich Syndrome Protein (N-WASP) plays a crucial role in...
Squamous cell carcinoma (SCC) is one of the most common forms of skin cancer in humans, and Neural Wiskott-Aldrich Syndrome Protein (N-WASP) plays a crucial role in epidermal homeostasis. To elucidate the role of N-WASP in skin cancer, we generated mice which expressed constitutively active KRas (KRas) in keratinocytes with either homozygous (N-WASP) or heterozygous (N-WASP) N-WASP knockout upon Tamoxifen (TAM) injection. Both the N-WASP and N-WASP mice had similar body weights and no congenital malformations prior to the injection of TAM. Within 2 weeks of the injections, the N-WASP mice exhibited significant reductions in weight coupled with visible tumors at numerous sites, unlike the N-WASP mice, which had no visible tumors. We found that both sets of mice had oily, sticky skin and wet eyes 3 weeks after their exposure to TAM, indicating the overproduction of sebum/meibum. At 37 days post TAM injection, several notable observations were made. Tumors collected from the N-WASP mice had small- to large-sized keratin pearls that were not observed in the N-WASP mice. A Western blot and immunostaining analysis both highlighted significantly higher levels of expression of SCC markers, such as the cytokeratins 8, 17, 18, and 19 and TP63, in the tumors of the N-WASP mice compared to those of the latter group. Furthermore, we noted increases in the expression levels of EGFR, P-ERK, GLUT1, P-mTOR, and P-4EBP in the N-WASP mice, suggesting that the deletion of N-WASP in the keratinocytes enhanced KRas signaling and glucose uptake, resulting in aggressive tumor formation. Interestingly, a thickening of the epidermal layer within the esophagus and tongue was only observed in the N-WASP mice. Immunostaining for PCNA emphasized a significantly higher number of PCNA-positive cells in the skin of the N-WASP mice compared to their counterparts, implying that epidermal thickening and enhanced tumorigenesis are due to an increased proliferation of keratinocytes. Through our results, we have established that N-WASP plays a tumor-suppressive role in skin cancer.
PubMed: 37760426
DOI: 10.3390/cancers15184455 -
Development (Cambridge, England) Feb 2024The 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 pezo-1[R2405P] that in human PIEZO2 causes distal arthrogryposis type 5 (DA5; p. R2718P). Electrophysiological analyses indicate that pezo-1(R2405P) is a gain-of-function allele. Using genomic mapping and whole-genome sequencing approaches, we identified a candidate suppressor allele in the C. elegans gene gex-3. This gene is an ortholog of human NCKAP1 (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 gex-3 by RNAi, or with the suppressor allele gex-3(av259[L353F]), significantly increased brood size and ovulation rate, as well as alleviating the crushed oocyte phenotype of the pezo-1(R2405P) mutant. Expression of GEX-3 in the soma is required to rescue the brood size defects in pezo-1(R2405P) animals. Actin organization and orientation were disrupted and distorted in the pezo-1 mutants. Mutation of gex-3(L353F) partially alleviated these defects. The identification of gex-3 as a suppressor of the pathogenic variant pezo-1(R2405P) suggests that the PIEZO coordinates with the cytoskeleton regulator to maintain the F-actin network and provides insight into the molecular mechanisms of DA5 and other PIEZO-associated diseases.
Topics: Animals; Female; Humans; Actins; Arthrogryposis; Caenorhabditis elegans; Ion Channels; Mutation; Ophthalmoplegia; Polymerization; Retinal Diseases
PubMed: 38349741
DOI: 10.1242/dev.202214 -
Cells Dec 2023Skeletal myogenesis is an intricate process involving the differentiation of progenitor cells into myofibers, which is regulated by actin cytoskeletal dynamics and...
Skeletal myogenesis is an intricate process involving the differentiation of progenitor cells into myofibers, which is regulated by actin cytoskeletal dynamics and myogenic transcription factors. Although recent studies have demonstrated the pivotal roles of actin-binding proteins (ABPs) as mechanosensors and signal transducers, the biological significance of WAVE2 (Wiskott-Aldrich syndrome protein family member 2), an ABP essential for actin polymerization, in myogenic differentiation of progenitor cells has not been investigated. Our study provides important insights into the regulatory roles played by WAVE2 in the myocardin-related transcription factor A (MRTFA)-serum response factor (SRF) signaling axis and differentiation of myoblasts. We demonstrate that WAVE2 expression is induced during myogenic differentiation and plays a pivotal role in actin cytoskeletal remodeling in C2C12 myoblasts. Knockdown of WAVE2 in C2C12 cells reduced filamentous actin levels, increased globular actin accumulation, and impaired the nuclear translocation of MRTFA. Furthermore, WAVE2 depletion in myoblasts inhibited the expression and transcriptional activity of SRF and suppressed cell proliferation in myoblasts. Consequently, WAVE2 knockdown suppressed myogenic regulatory factors (i.e., MyoD, MyoG, and SMYD1) expressions, thereby hindering the differentiation of myoblasts. Thus, this study suggests that WAVE2 is essential for myogenic differentiation of progenitor cells by modulating the mechanosensitive MRTFA-SRF axis.
Topics: Actins; Nuclear Proteins; Serum Response Factor; Stem Cells; Trans-Activators; Animals; Mice
PubMed: 38201213
DOI: 10.3390/cells13010009