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Soohee Lee - One of the best experts on this subject based on the ideXlab platform.
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THE KELL AND KX BLOOD GROUP SYSTEMS
2015Co-Authors: Soohee LeeAbstract:ell is a major human blood group system that is highly polymorphic, and at present it is known to express 28 different alloantigens. After the ABO and Rh systems, Kell is themost important blood group system in transfusion medicine, as some of the antigens are potent immunogens and their antibodies can cause severe transfusion reactions in mismatched blood transfusions and fetal anemia in feto-maternal incompatible pregnancies. The Kx blood group system is composed of a single antigen, Kx, which is carried on the XK Protein. This system is important clinically because absence of XK Protein, found in rare McLeod phenotypes, leads to red blood cell (RBC) acanthocytosis and to late onset abnor-malities, usually commencing aboutmidlife, involving th
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Two McLeod patients with novel mutations in XK.
Journal of the neurological sciences, 2011Co-Authors: Patrycja M Dubielecka, Nelson Hwynn, Cenk Sengun, Soohee Lee, Christine Lomas-francis, Carlos Singer, Hubert H Fernandez, Ruth H WalkerAbstract:McLeod syndrome (MLS) is a rare, X-linked, late-onset, disease involving hematological, brain, and neuromuscular systems, caused by mutations in XK that result in either defective XK or complete loss of XK Protein. Acanthocytosis of erythrocytes is a typical feature. We report novel mutations in two patients who exhibited typical clinical characteristics of MLS. The coding and flanking intronic regions of XK were amplified by PCR, sequenced, and compared with the normal XK sequence. XK Protein, and its complexed partner Protein, Kell, were assessed by Western blot analysis. Patient 1 was found to have a single base insertion, 605insA at 175Ile creating a frame shift within the coding sequence of XK. Patient 2 had a single base substitution in the 3' splice sequence of intron 2 (IVS2-2a>g). In both cases mutations resulted in the absence of XK Protein.
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Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases.
Gene, 2007Co-Authors: Jianbin Peng, Ruth H Walker, Colvin M. Redman, Xiaoling Song, Connie M. Westhoff, Soohee LeeAbstract:Abstract The McLeod phenotype is derived from various forms of XK gene defects that result in the absence of XK Protein, and is defined hematologically by the absence of Kx antigen, weakening of Kell system antigens, and red cell acanthocytosis. Individuals with the McLeod phenotype usually develop late-onset neuromuscular abnormalities known as the McLeod syndrome (MLS). MLS is an X-linked multi-system disorder caused by absence of XK alone, or when the disorder is caused by large deletions, it may be accompanied with Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CYBB), retinitis pigmentosa (RPGR), and ornithine transcarbamylase deficiency (OTC). XK defects derived from a large deletion at the XK locus (Xp21.1) have not been characterized at the molecular level. In this study, the deletion breakpoints of two novel cases of McLeod phenotype with extensive deletions are reported. Case 1 has greater than 1.12 million base-pairs (mb) deletion around the XK locus with 7 genes affected. Case 2 has greater than 5.65 mb deletion from TCTE1L to DMD encompassing 20 genes. Phylogenetic analyses demonstrated that DMD, XK and CYBB have close paralogs, some of which may partially substitute for the functions of their counterparts. The loci around XK are highly conserved from fish to human; however, the disorders are probably specific to mammals, and may coincide with the translocation of the loci to the X chromosome after the speciation in birds. The non-synonymous to synonymous nucleotide substitution rate ratio (ω = dN/dS) in these genes was examined. CYBB and RPGR show evidence of positive selection, whereas DMD, XK and OTC are subject to selective constraint.
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Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases.
Gene, 2007Co-Authors: Jianbin Peng, Ruth H Walker, Colvin M. Redman, Xiaoling Song, Connie M. Westhoff, Soohee LeeAbstract:The McLeod phenotype is derived from various forms of XK gene defects that result in the absence of XK Protein, and is defined hematologically by the absence of Kx antigen, weakening of Kell system antigens, and red cell acanthocytosis. Individuals with the McLeod phenotype usually develop late-onset neuromuscular abnormalities known as the McLeod syndrome (MLS). MLS is an X-linked multi-system disorder caused by absence of XK alone, or when the disorder is caused by large deletions, it may be accompanied with Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CYBB), retinitis pigmentosa (RPGR), and ornithine transcarbamylase deficiency (OTC). XK defects derived from a large deletion at the XK locus (Xp21.1) have not been characterized at the molecular level. In this study, the deletion breakpoints of two novel cases of McLeod phenotype with extensive deletions are reported. Case 1 has greater than 1.12 million base-pairs (mb) deletion around the XK locus with 7 genes affected. Case 2 has greater than 5.65 mb deletion from TCTE1L to DMD encompassing 20 genes. Phylogenetic analyses demonstrated that DMD, XK and CYBB have close paralogs, some of which may partially substitute for the functions of their counterparts. The loci around XK are highly conserved from fish to human; however, the disorders are probably specific to mammals, and may coincide with the translocation of the loci to the X chromosome after the speciation in birds. The non-synonymous to synonymous nucleotide substitution rate ratio (omega=dN/dS) in these genes was examined. CYBB and RPGR show evidence of positive selection, whereas DMD, XK and OTC are subject to selective constraint.
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The value of DNA analysis for antigens of the Kell and Kx blood group systems.
Transfusion, 2007Co-Authors: Soohee LeeAbstract:K ell is a major human blood group system that is highly polymorphic, and at present it is known to express 28 different alloantigens. After the ABO and Rh systems, Kell is the most important blood group system in transfusion medicine, as some of the antigens are potent immunogens and their antibodies can cause severe transfusion reactions in mismatched blood transfusions and fetal anemia in feto-maternal incompatible pregnancies. The Kx blood group system is composed of a single antigen, Kx, which is carried on the XK Protein. This system is important clinically because absence of XK Protein, found in rare McLeod phenotypes, leads to red blood cell (RBC) acanthocytosis and to late onset abnormalities, usually commencing about midlife, involving the peripheral and central nervous systems, known as the McLeod syndrome.
Hans H. Jung - One of the best experts on this subject based on the ideXlab platform.
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identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis. PLoS One 2012
2016Co-Authors: Lucia De Franceschi, Ruth H Walker, Hans H. Jung, Giovanni Scardoni, Carlo Tomelleri, Adrian Danek, Benedikt Bader, Sara Mazzucco, Maria Teresa Dotti, Angela SicilianoAbstract:Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane Protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, XK Protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein Protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, Protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related Protein-Protein interaction networks b
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Computational Identification of Phospho-Tyrosine Sub- Networks Related to Acanthocyte Generation in
2016Co-Authors: Lucia De Franceschi, Ruth H Walker, Hans H. Jung, Giovanni Scardoni, Carlo Tomelleri, Adrian Danek, Benedikt Bader, Sara Mazzucco, Maria Teresa Dotti, Angela SicilianoAbstract:Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane Protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, XK Protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein Protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, Protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related Protein-Protein interaction networks b
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Computational Identification of Phospho-Tyrosine Sub-Networks Related to Acanthocyte Generation in Neuroacanthocytosis
PloS one, 2012Co-Authors: Lucia De Franceschi, Ruth H Walker, Hans H. Jung, Giovanni Scardoni, Carlo Tomelleri, Adrian Danek, Benedikt Bader, Sara Mazzucco, Maria Teresa Dotti, Angela SicilianoAbstract:Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane Protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, XK Protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein Protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, Protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related Protein-Protein interaction networks by identifying all the interactomic shortest paths linking XK and chorein to the corresponding set of Proteins whose tyrosine phosphorylation was altered in patients. These networks include the most likely paths of functional influence of XK and chorein on phosphorylated Proteins. We further refined the analysis by extracting restricted sets of highly interacting signaling Proteins representing a common molecular background bridging the generation of acanthocytes in MLS and ChAc. The final analysis pointed to a novel, very restricted, signaling module of 14 highly interconnected kinases, whose alteration is possibly involved in generation of acanthocytes in MLS and ChAc.
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McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement.
Transfusion, 2003Co-Authors: Hans H. Jung, David Russo, Martin Hergersberg, Marco Vogt, Jens Pahnke, Valerie Treyer, Benno Röthlisberger, Spyros Kollias, Beat M. FreyAbstract:BACKGROUND: The X-linked McLeod neuroacanthocytosis syndrome is a multisystem disorder with hematologic, neuromuscular, and central nervous system (CNS) manifestations. All carriers of the McLeod blood group phenotype examined so far had at least subclinical signs of systemic involvement. STUDY DESIGN AND METHODS: Evaluation of two brothers carrying the McLeod phenotype with neurologic examination, immunohematology, RBC membrane Protein Western blotting, analysis of XK DNA sequence and RNA levels, muscle histology including XK/Kell immunohistochemistry, cerebral magnetic resonance imaging (MRI), and quantified positron emission tomography (PET). RESULTS: Immunohematology and Western blotting confirmed presence of the McLeod blood group phenotype. No acanthocytosis or other hematologic anomalies were found. XK gene sequence analysis revealed a missense mutation in exon 3 (E327K). WBC XK RNA levels were not decreased. There were no neuromuscular and CNS signs or symptoms. In addition, no subclinical involvement was discovered on the basis of normal muscle histology with a physiologic pattern of XK and Kell immunohistochemistry, normal cerebral MRI, and quantified PET. CONCLUSION: Known disease-causing XK gene mutations comprised deletions, nonsense, or splice-site mutations predicting absent or truncated XK Protein devoid of the Kell-Protein binding site. Although the E327K missense mutation was associated with the immunohematologic characteristics of McLeod syndrome, the mutated XK Protein seemed to be largely functional. These findings contribute to the understanding of the physiology of XK and Kell Proteins, and the pathogenetic mechanisms of acanthocytosis, myopathy, and striatal neurodegeneration in McLeod syndrome.
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Mcleod syndrome: A novel mutation, predominant psychiatric manifestations, and distinct striatal imaging findings
Annals of neurology, 2001Co-Authors: Hans H. Jung, Martin Hergersberg, Spyros Kollias, Stefan Kneifel, Hatem Alkadhi, Regula Schiess, Maike Weigell-weber, Geoff Daniels, Klaus HessAbstract:The McLeod syndrome is an X-linked disorder caused by mutations of the XK gene encoding the XK Protein. The syndrome is characterized by absent Kx erythrocyte antigen, weak expression of Kell blood group system antigens, and acanthocytosis. In some allelic variants, elevated creatine kinase, myopathy, neurogenic muscle atrophy, and progressive chorea are found. We describe a family with a novel point mutation in the XK gene consisting of a C to T base transition at nucleotide position 977, introducing a stop codon. Among seven affected males, five manifested with psychiatric disorders such as depression, bipolar disorder, or personality disorder, but only two presented with chorea. Positron emission tomography and magnetic resonance volumetry revealed reduced striatal 2-fluoro-2-deoxy-glucose (FDG) uptake and diminished volumes of the caudate nucleus and putamen that correlated with disease duration. In contrast, none of 12 female mutation carriers showed psychiatric or movement disorders. However, a semidominant effect of the mutation was suggested by erythrocyte and blood group mosaicism and reduced striatal FDG uptake without structural abnormalities. Therefore, patients with psychiatric signs or symptoms segregating in an X-linked trait should be examined for acanthocytosis and Kell/Kx blood group serology. Ann Neurol 2001;49:384–392
Ruth H Walker - One of the best experts on this subject based on the ideXlab platform.
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identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis. PLoS One 2012
2016Co-Authors: Lucia De Franceschi, Ruth H Walker, Hans H. Jung, Giovanni Scardoni, Carlo Tomelleri, Adrian Danek, Benedikt Bader, Sara Mazzucco, Maria Teresa Dotti, Angela SicilianoAbstract:Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane Protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, XK Protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein Protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, Protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related Protein-Protein interaction networks b
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Computational Identification of Phospho-Tyrosine Sub- Networks Related to Acanthocyte Generation in
2016Co-Authors: Lucia De Franceschi, Ruth H Walker, Hans H. Jung, Giovanni Scardoni, Carlo Tomelleri, Adrian Danek, Benedikt Bader, Sara Mazzucco, Maria Teresa Dotti, Angela SicilianoAbstract:Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane Protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, XK Protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein Protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, Protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related Protein-Protein interaction networks b
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Computational Identification of Phospho-Tyrosine Sub-Networks Related to Acanthocyte Generation in Neuroacanthocytosis
PloS one, 2012Co-Authors: Lucia De Franceschi, Ruth H Walker, Hans H. Jung, Giovanni Scardoni, Carlo Tomelleri, Adrian Danek, Benedikt Bader, Sara Mazzucco, Maria Teresa Dotti, Angela SicilianoAbstract:Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane Protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, XK Protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein Protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, Protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related Protein-Protein interaction networks by identifying all the interactomic shortest paths linking XK and chorein to the corresponding set of Proteins whose tyrosine phosphorylation was altered in patients. These networks include the most likely paths of functional influence of XK and chorein on phosphorylated Proteins. We further refined the analysis by extracting restricted sets of highly interacting signaling Proteins representing a common molecular background bridging the generation of acanthocytes in MLS and ChAc. The final analysis pointed to a novel, very restricted, signaling module of 14 highly interconnected kinases, whose alteration is possibly involved in generation of acanthocytes in MLS and ChAc.
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Two McLeod patients with novel mutations in XK.
Journal of the neurological sciences, 2011Co-Authors: Patrycja M Dubielecka, Nelson Hwynn, Cenk Sengun, Soohee Lee, Christine Lomas-francis, Carlos Singer, Hubert H Fernandez, Ruth H WalkerAbstract:McLeod syndrome (MLS) is a rare, X-linked, late-onset, disease involving hematological, brain, and neuromuscular systems, caused by mutations in XK that result in either defective XK or complete loss of XK Protein. Acanthocytosis of erythrocytes is a typical feature. We report novel mutations in two patients who exhibited typical clinical characteristics of MLS. The coding and flanking intronic regions of XK were amplified by PCR, sequenced, and compared with the normal XK sequence. XK Protein, and its complexed partner Protein, Kell, were assessed by Western blot analysis. Patient 1 was found to have a single base insertion, 605insA at 175Ile creating a frame shift within the coding sequence of XK. Patient 2 had a single base substitution in the 3' splice sequence of intron 2 (IVS2-2a>g). In both cases mutations resulted in the absence of XK Protein.
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Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases.
Gene, 2007Co-Authors: Jianbin Peng, Ruth H Walker, Colvin M. Redman, Xiaoling Song, Connie M. Westhoff, Soohee LeeAbstract:Abstract The McLeod phenotype is derived from various forms of XK gene defects that result in the absence of XK Protein, and is defined hematologically by the absence of Kx antigen, weakening of Kell system antigens, and red cell acanthocytosis. Individuals with the McLeod phenotype usually develop late-onset neuromuscular abnormalities known as the McLeod syndrome (MLS). MLS is an X-linked multi-system disorder caused by absence of XK alone, or when the disorder is caused by large deletions, it may be accompanied with Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CYBB), retinitis pigmentosa (RPGR), and ornithine transcarbamylase deficiency (OTC). XK defects derived from a large deletion at the XK locus (Xp21.1) have not been characterized at the molecular level. In this study, the deletion breakpoints of two novel cases of McLeod phenotype with extensive deletions are reported. Case 1 has greater than 1.12 million base-pairs (mb) deletion around the XK locus with 7 genes affected. Case 2 has greater than 5.65 mb deletion from TCTE1L to DMD encompassing 20 genes. Phylogenetic analyses demonstrated that DMD, XK and CYBB have close paralogs, some of which may partially substitute for the functions of their counterparts. The loci around XK are highly conserved from fish to human; however, the disorders are probably specific to mammals, and may coincide with the translocation of the loci to the X chromosome after the speciation in birds. The non-synonymous to synonymous nucleotide substitution rate ratio (ω = dN/dS) in these genes was examined. CYBB and RPGR show evidence of positive selection, whereas DMD, XK and OTC are subject to selective constraint.
Lucia De Franceschi - One of the best experts on this subject based on the ideXlab platform.
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identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis. PLoS One 2012
2016Co-Authors: Lucia De Franceschi, Ruth H Walker, Hans H. Jung, Giovanni Scardoni, Carlo Tomelleri, Adrian Danek, Benedikt Bader, Sara Mazzucco, Maria Teresa Dotti, Angela SicilianoAbstract:Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane Protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, XK Protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein Protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, Protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related Protein-Protein interaction networks b
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Computational Identification of Phospho-Tyrosine Sub- Networks Related to Acanthocyte Generation in
2016Co-Authors: Lucia De Franceschi, Ruth H Walker, Hans H. Jung, Giovanni Scardoni, Carlo Tomelleri, Adrian Danek, Benedikt Bader, Sara Mazzucco, Maria Teresa Dotti, Angela SicilianoAbstract:Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane Protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, XK Protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein Protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, Protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related Protein-Protein interaction networks b
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Abnormal red cell features associated with hereditary neurodegenerative disorders: the neuroacanthocytosis syndromes.
Current opinion in hematology, 2014Co-Authors: Lucia De Franceschi, Giel J. C. G. M. Bosman, Narla MohandasAbstract:PURPOSE OF REVIEW: This review discusses the mechanisms involved in the generation of thorny red blood cells (RBCs), known as acanthocytes, in patients with neuroacanthocytosis, a heterogenous group of neurodegenerative hereditary disorders that include chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). RECENT FINDINGS: Although molecular defects associated with neuroacanthocytosis have been identified recently, their pathophysiology and the related RBC abnormalities are largely unknown. Studies in ChAc RBCs have shown an altered association between the cytoskeleton and the integral membrane Protein compartment in the absence of major changes in RBC membrane composition. In ChAc RBCs, abnormal Lyn kinase activation in a Syk-independent fashion has been reported recently, resulting in increased band 3 tyrosine phosphorylation and perturbation of the stability of the multiProtein band 3-based complexes bridging the membrane to the spectrin-based membrane skeleton. Similarly, in MLS, the absence of XK-Protein, which is associated with the spectrin-actin-4.1 junctional complex, is associated with an abnormal membrane Protein phosphorylation state, with destabilization of the membrane skeletal network resulting in generation of acanthocytes. SUMMARY: A novel mechanism in generation of acanthocytes involving abnormal Lyn activation, identified in ChAc, expands the acanthocytosis phenomenon toward Protein-Protein interactions, controlled by phosphorylation-related abnormal signaling.
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Computational Identification of Phospho-Tyrosine Sub-Networks Related to Acanthocyte Generation in Neuroacanthocytosis
PloS one, 2012Co-Authors: Lucia De Franceschi, Ruth H Walker, Hans H. Jung, Giovanni Scardoni, Carlo Tomelleri, Adrian Danek, Benedikt Bader, Sara Mazzucco, Maria Teresa Dotti, Angela SicilianoAbstract:Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane Protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, XK Protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein Protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, Protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related Protein-Protein interaction networks by identifying all the interactomic shortest paths linking XK and chorein to the corresponding set of Proteins whose tyrosine phosphorylation was altered in patients. These networks include the most likely paths of functional influence of XK and chorein on phosphorylated Proteins. We further refined the analysis by extracting restricted sets of highly interacting signaling Proteins representing a common molecular background bridging the generation of acanthocytes in MLS and ChAc. The final analysis pointed to a novel, very restricted, signaling module of 14 highly interconnected kinases, whose alteration is possibly involved in generation of acanthocytes in MLS and ChAc.
Marion E. Reid - One of the best experts on this subject based on the ideXlab platform.
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Chapter 21 – Kx blood group system
The Blood Group Antigen FactsBook, 2004Co-Authors: Marion E. Reid, Christine Lomas-francisAbstract:Publisher Summary This chapter discusses the Kx blood group system. The terminology, expression, database accession numbers, and the carrier molecule related to the Kx blood group system are also reviewed. This blood group was named in 1990 when the Kx antigen was assigned system status. In the red blood cell (RBC) membrane, XK Protein (Kx Protein) is covalently linked at Cys 72 to Cys 347 of the Kell glycoProtein. The function and disease association of the Kx blood group system is also discussed. XK has structural characteristics of a membrane transport Protein, and a homolog, ced-8, is involved in regulating cell death in C. elegans. XK is involved in the maintenance of normal cell membrane integrity. Absence of XK Protein is associated with acanthocytosis and the McLeod syndrome, which manifests a compensated hemolytic anemia, elevated serum creatinine kinase and neuromuscular disorders including chorea, areflexia, skeletal muscle atrophy and cardiomyopathy.
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Chapter 8 – Kell blood group system
The Blood Group Antigen FactsBook, 2004Co-Authors: Marion E. Reid, Christine Lomas-francisAbstract:Publisher Summary This chapter discusses the Kell blood group system. The terminology, expression, database accession numbers, and the carrier molecule related to the Kell blood group system are also reviewed. The Kell blood group was named in 1946 after the first antibody producer (Kelleher) of anti-K that caused HDN. The carrier molecule is a single-pass red blood cell (RBC) membrane glycoProtein (type II) that is highly folded via disulphide bonds. In the RBC membrane Kell glycoProtein is covalently linked at Cys72 to the Cys347 of the XK Protein. The function and disease association of the Kell blood group system is also reviewed. Kell glycoProtein is an endothelin-3-converting enzyme, preferentially cleaving big endothelin-3, a 41 amino acid polypeptide, at Trp21-Ile22, creating bioactive endothelin-3, a potent vasoconstrictor. Kell, in common with all zinc endopeptidases, shares a pentameric sequence, HEXXH, which is central to zinc binding and catalytic activity.
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First example of anti-Kx in a person with the McLeod phenotype and without chronic granulomatous disease
Transfusion, 2000Co-Authors: David Russo, Colvin M. Redman, Ragnhild Øyen, Vivien I. Powell, Sherry Perry, Judith Hitchcock, Marion E. ReidAbstract:BACKGROUND: Kx is lacking in the RBCs of patients with the McLeod syndrome. This condition is sometimes associated with chronic granulomatous disease (CGD). If given allogeneic RBCs, CGD patients with the McLeod phenotype may produce anti-Kx and anti-Km, and only phenotypically matched McLeod blood would be compatible. McLeod phenotype persons without CGD have made anti-Km but not anti-Kx (2 examples), and thus both McLeod and KO blood would be compatible. CASE REPORT: RBCs from a transfused patient with the McLeod phenotype but not with CGD (non-CGD McLeod) were typed for the Kell blood group antigens, and the plasma was analyzed for the presence of antibody by agglutination. The molecular basis was determined by analyzing for XK Protein on RBC membranes by Western immunoblotting, by sequencing the XK gene, and by RFLP. RESULTS: The RBCs did not react with anti-Kx + anti-Km and showed weakening of Kell system antigens. The patient′s plasma reacted moderately (2+) with RBCs of common Kell type and strongly (4+) with KO RBCs and RBCs of common Kell type treated with dithiothreitol, and did not react with McLeod RBCs. XK Protein was absent from the RBC membranes. The XK gene had a point mutation in the donor splice site of intron 1 (G>C). CONCLUSION: This is the first report describing the molecular alteration in a non-CGD McLeod patient who has made anti-Kx. The immune response of people with the McLeod phenotype can vary, and KO blood may not always be compatible.
