Hematologically important mutations: Leukocyte adhesion deficiency (second update)

Roos, Dirk; Leeuwen, Karin van; Madkaikar, Manisha; Kambli, Priyanka; Gupta, Maya; Rawat, Amit; Kuhns, Douglas B.; Holland, Steven M.; Boer, Martin de; Kanegane, Hirokazu; Parvaneh, Nima; Lorenz, Myriam Ricarda; Schwarz, Klaus; Klein, Christoph; Sherkat, Roya; Jafari, Mahbube; Wolach, Baruch; Dunnen, Johan T. den; Kuijpers, Taco W.; Köker, Mustafa Yavuz

doi:10.1016/j.bcmd.2023.102726

Cited by 14 publications

(13 citation statements)

References 93 publications

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“…According to the last update of mutations reported by Roos et al in 2023, over 170 mutations have been detected in the ITGB2 gene so far, of which single-nucleotide substitutions (i.e., missense, nonsense, and splice site defect) are the most frequent; this is followed by small deletions. 30 This is in line with our study results. and function of integrins have been shown in a few variants that reclassified them as polymorphisms.…”

Section: Discussionsupporting

confidence: 93%

“…The most frequent mutations were missense and nonsense in this study. According to the last update of mutations reported by Roos et al in 2023, over 170 mutations have been detected in the ITGB2 gene so far, of which single‐nucleotide substitutions (i.e., missense, nonsense, and splice site defect) are the most frequent; this is followed by small deletions 30 . This is in line with our study results.…”

Section: Discussionsupporting

confidence: 91%

“…The novel mutation, p.Tyr530*, was previously reported as a result of c.1590C>G mutation. It caused the substitution of the third nucleotide of the TAC codon with G and created the TAG termination codon 30 while in our study, the deletion of five nucleotides CGGGC from position 1590 to 1594 causes the positioning of the second nucleotide of the CAG codon corresponding to the Glutamine532 residue next to the two nucleotides TA of Tyrosine530 and makes the termination codon TAA. Therefore, this mutation was presented as a novel mutation in our study.…”

Section: Discussionmentioning

confidence: 44%

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Clinical and immunological characteristics of 69 leukocyte adhesion deficiency‐I patients

Fazlollahi,

Hamidieh,

Moradi

et al. 2023

Pediatric Allergy Immunology

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Background In order to support the comprehensive classification of Leukocyte Adhesion Deficiency‐I (LAD‐I) severity by simultaneous screening of CD11a/CD18, this study assessed clinical, laboratory, and genetic findings along with outcomes of 69 LAD‐I patients during the last 15 years. Methods Sixty‐nine patients (40 females and 29 males) with a clinical phenotype suspected of LAD‐I were referred to Immunology, Asthma, and Allergy research institute, Tehran, Iran between 2007 and 2022 for further advanced immunological screening and genetic evaluations as well as treatment, were enrolled in this study. Results The diagnosis median age of the patients was 6 months. Delayed umbilical cord separation was found in 25 patients (36.2%). The median diagnostic delay time was 4 months (min–max: 0–82 months). Forty‐six patients (66.7%) were categorized as severe (CD18 and/or CD11a: below 2%); while 23 children (33.3%) were in moderate category (CD18 and/or CD11a: 2%–30%). During the follow‐ups, 55.1% of children were alive with a mortality rate of 44.9%. Skin ulcers (75.4%), omphalitis (65.2%), and gingivitis (37.7%) were the most frequent complaints. Genetic analysis of the patients revealed 14 previously reported and three novel pathogenic mutations in the ITGB2 gene. The overall survival of patients with and without hematopoietic stem cell transplantation was 79.3% and 55.6%, respectively. Conclusion Physicians' awareness of LAD‐I considering delayed separation of umbilical cord marked neutrophilic leukocytosis, and variability in CD11 and CD18 expression levels, and genetic analysis leads to early diagnosis and defining disease severity. Moreover, the prenatal diagnosis would benefit families with a history of LAD‐I.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 44%

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Clinical and immunological characteristics of 69 leukocyte adhesion deficiency‐I patients

Fazlollahi,

Hamidieh,

Moradi

et al. 2023

Pediatric Allergy Immunology

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“…FERMT3 worked as an activator of immune-related pathways and inflammatory cell infiltration . In all blood cells, FERMT3 encodes the kindlin-3 protein, which enables it to participate in the regulation of integrin conformation . Platelet membranes GP IIb (CD41) or GP IIIa (CD61), also known as integrin αIIbβ3, are encoded by the ITGA2B and ITGB3 genes, respectively.…”

Section: Discussionmentioning

confidence: 99%

Vinculin Identified as a Potential Biomarker in Hand-Arm Vibration Syndrome Based on iTRAQ and LC–MS/MS-Based Proteomic Analysis

et al. 2023

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Local vibration can induce vascular injuries, one example is the hand-arm vibration syndrome (HAVS) caused by hand-transmitted vibration (HTV). Little is known about the molecular mechanism of HAVS-induced vascular injuries. Herein, the iTRAQ (isobaric tags for relative and absolute quantitation) followed by liquid chromatography−tandem mass spectrometry (LC−MS/MS) proteomics approach was applied to conduct the quantitative proteomic analysis of plasma from specimens with HTV exposure or HAVS diagnosis. Overall, 726 proteins were identified in iTRAQ. 37 proteins upregulated and 43 downregulated in HAVS. Moreover, 37 upregulated and 40 downregulated when comparing severe HAVS and mild HAVS. Among them, Vinculin (VCL) was found to be downregulated in the whole process of HAVS. The concentration of vinculin was further verified by ELISA, and the results suggested that the proteomics data was reliable. Bioinformative analyses were used, and those proteins mainly engaged in specific biological processes like binding, focal adhesion, and integrins. The potential of vinculin application in HAVS diagnosis was validated by the receiver operating characteristic curve.

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“…45,46 CGD is characterized by development of intestinal tissue granulomas and inflammation in approximately 40% of cases. 47 Other genes identified as monogenic disorders of bacterial clearance associated with VEOIBD include ITGB2 (leukocyte adhesion deficiency type 1, LAD type 1) 48 and SLC35C1 (LAD type 2), 49 which can present with IBD and history of bacterial infections and increased granulocytes; RAC2, whose product RAC2 interacts with the NCF2 protein found mutated in CGD, 50 can present in the neonatal period as IBD; Glycogen storage disease Type 1b, 51 which presents with neutrophil dysfunction and neutropenia associated with intestinal inflammation.…”

Section: Innate Immune Defects/bacterial Clearance and Recognitionmentioning

confidence: 99%

Understanding very early onset inflammatory bowel disease (VEOIBD) in relation to inborn errors of immunity

Hall,

de Zoeten

2023

Immunological Reviews

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SummaryInflammatory bowel diseases (IBD) are multifactorial diseases which are caused by the combination of genetic predisposition, exposure factors (environmental and dietary), immune status, and dysbiosis. IBD is a disease which presents at any age, ranging from newborns to the elderly. The youngest of the pediatric IBD population have a more unique presentation and clinical course and may have a different etiology. Very early onset IBD (VEOIBD) patients, designated as those diagnosed prior the age of 6, have distinct features which are more frequent in this patient population including increased incidence of monogenetic causes for IBD (0%–33% depending on the study). This proportion is increased in the youngest subsets, which is diagnosed prior to the age of 2. To date, there are approximately 80 monogenic causes of VEOIBD that have been identified and published. Many of these monogenic causes are inborn errors of immunity yet the majority of VEOIBD patients do not have an identifiable genetic cause for their disease. In this review, we will focus on the clinical presentation, evaluation, and monogenic categories which have been associated with VEOIBD including (1) Epithelial cell defects (2) Adaptive immune defects, (3) Innate Immune/Bacterial Clearance and Recognition defects, and (4) Hyperinflammatory and autoinflammatory disorders. We will highlight differential diagnosis of VEOIBD presentations, as well as evaluation and treatment, which will be helpful for those who study and care for VEOIBD patients outside of the pediatric gastroenterology field. This is a fast‐moving field of research which has grown significantly based on knowledge that we gain from our patients. These scientific findings have identified novel mucosal biology pathways and will continue to inform our understanding of gastrointestinal biology.

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Hematologically important mutations: Leukocyte adhesion deficiency (second update)

Cited by 14 publications

References 93 publications

Clinical and immunological characteristics of 69 leukocyte adhesion deficiency‐I patients

Clinical and immunological characteristics of 69 leukocyte adhesion deficiency‐I patients

Vinculin Identified as a Potential Biomarker in Hand-Arm Vibration Syndrome Based on iTRAQ and LC–MS/MS-Based Proteomic Analysis

Understanding very early onset inflammatory bowel disease (VEOIBD) in relation to inborn errors of immunity

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