The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Attila Kumanovics - One of the best experts on this subject based on the ideXlab platform.

  • a novel germline PIGA mutation in ferro cerebro cutaneous syndrome a neurodegenerative x linked epileptic encephalopathy with systemic iron overload
    American Journal of Medical Genetics Part A, 2014
    Co-Authors: Kathryn J Swoboda, Rebecca L Margraf, John C Carey, Holly Zhou, Tara M Newcomb, Emily M Coonrod, Jacob D Durtschi, Kalyan Mallempati, Attila Kumanovics
    Abstract:

    Three related males presented with a newly recognized x-linked syndrome associated with neurodegeneration, cutaneous abnormalities, and systemic iron overload. Linkage studies demonstrated that they shared a haplotype on Xp21.3-Xp22.2 and exome sequencing was used to identify candidate variants. Of the segregating variants, only a PIGA mutation segregated with disease in the family. The c.328_330delCCT PIGA variant predicts, p.Leu110del (or c.1030_1032delCTT, p.Leu344del depending on the reference sequence). The unaffected great-grandfather shared his X allele with the proband but he did not have the PIGA mutation, indicating that the mutation arose de novo in his daughter. A single family with a germline PIGA mutation has been reported; affected males had a phenotype characterized by multiple congenital anomalies and severe neurologic impairment resulting in infantile lethality. In contrast, affected boys in the family described here were born without anomalies and were neurologically normal prior to onset of seizures after 6 months of age, with two surviving to the second decade. PIGA encodes an enzyme in the GPI anchor biosynthesis pathway. An affected individual in the family studied here was deficient in GPI anchor proteins on granulocytes but not erythrocytes. In conclusion, the PIGA mutation in this family likely causes a reduction in GPI anchor protein cell surface expression in various cell types, resulting in the observed pleiotropic phenotype involving central nervous system, skin, and iron metabolism.

  • a novel germline PIGA mutation in ferro cerebro cutaneous syndrome a neurodegenerative x linked epileptic encephalopathy with systemic iron overload
    American Journal of Medical Genetics Part A, 2014
    Co-Authors: Kathryn J Swoboda, Rebecca L Margraf, John C Carey, Holly Zhou, Tara M Newcomb, Emily M Coonrod, Jacob D Durtschi, Kalyan Mallempati, Attila Kumanovics
    Abstract:

    Three related males presented with a newly recognized x-linked syndrome associated with neurodegeneration, cutaneous abnormalities, and systemic iron overload. Linkage studies demonstrated that they shared a haplotype on Xp21.3–Xp22.2 and exome sequencing was used to identify candidate variants. Of the segregating variants, only a PIGA mutation segregated with disease in the family. The c.328_330delCCT PIGA variant predicts, p.Leu110del (or c.1030_1032delCTT, p.Leu344del depending on the reference sequence). The unaffected great-grandfather shared his X allele with the proband but he did not have the PIGA mutation, indicating that the mutation arose de novo in his daughter. A single family with a germline PIGA mutation has been reported; affected males had a phenotype characterized by multiple congenital anomalies and severe neurologic impairment resulting in infantile lethality. In contrast, affected boys in the family described here were born without anomalies and were neurologically normal prior to onset of seizures after 6 months of age, with two surviving to the second decade. PIGA encodes an enzyme in the GPI anchor biosynthesis pathway. An affected individual in the family studied here was deficient in GPI anchor proteins on granulocytes but not erythrocytes. In conclusion, the PIGA mutation in this family likely causes a reduction in GPI anchor protein cell surface expression in various cell types, resulting in the observed pleiotropic phenotype involving central nervous system, skin, and iron metabolism. © 2013 Wiley Periodicals, Inc.

Monica Bessler - One of the best experts on this subject based on the ideXlab platform.

  • a novel mechanism of complement independent clearance of red cells deficient in glycosyl phosphatidylinositol linked proteins
    Blood, 2004
    Co-Authors: Marek Jasinski, Panagiotis Pantazopoulos, Russell P Rother, Nico Van Rooijen, Wenchao Song, Hector Molina, Monica Bessler
    Abstract:

    Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by the increased sensitivity of red blood cells (RBCs) to complement, leading to intravascular hemolysis and hemoglobinuria. PNH is due to the expansion of a cell clone that has acquired a mutation in the PIGA gene. Mice with targeted PIGA gene inactivation genetically mimic the human disease and have phosphatidylinositol glycan class A-negative (PIGA-) RBCs with a reduced half-life in circulation. Although PIGA-RBCs are hypersensitive to complement in vitro, their complement sensitivity in vivo is barely detectable. Here we show that the shortened survival of PIGA- RBCs is independent of complement either by using inhibitory C5 antibodies or by transfusion into C5-, C4-, C3-, or factor B-deficient mice. Splenectomy or high-dose cortisone treatment had no effect on the shorter survival of PIGA- RBCs. However, treatment with liposome-encapsulated clodronate, an agent that depletes macrophages in vivo, normalized the half-life of PIGA- RBCs. This indicates that the shortened survival of PIGA- RBCs is due to a novel pathway of PIGA- RBC clearance that is mediated by macrophages, but occurs independently of complement. Future investigations will show whether this novel pathway of PIGA- RBC destruction identified in mice may also operate in patients with PNH. (Blood. 2004;103:2827-2834)

  • g csf induced progenitor mobilization in mice with PIGA blood cells
    Hematology Journal, 2004
    Co-Authors: Bing Han, Jacqueline Unsinger, Fulu Liu, Daniel C Link, Monica Bessler
    Abstract:

    OBJECTIVE In patients with paroxysmal nocturnal hemoglobinuria (PNH) a proportion of blood cells are deficient in glycosyl phosphatidylinositol (GPI) anchored proteins due to a mutation in the PIGA gene. Previous studies showed that in PNH the majority of circulating early progenitor cells were normal but after G-CSF were mainly, of the PNH phenotype. This suggested that GPI-linked proteins contribute to the regulation of progenitor trafficking from bone marrow to peripheral blood. METHODS To test this hypothesis we studied progenitor cells in bone marrow, spleen, and peripheral blood in response to G-CSF in mice genetically engineered to have a proportion of blood cells deficient in GPI-linked proteins (LF mice). RESULTS In contrast to humans, LF and wild-type mice have comparable numbers of progenitor cells in bone marrow, spleen, and peripheral blood. Similarly, in LF mice the proportion of PIGA- progenitor cells in peripheral blood corresponds the proportion of PIGA- progenitor cells measured in bone marrow and spleen. After G-CSF the number of circulating progenitors significantly increased but the proportion of PIGA- cells remained the same in peripheral blood,bone marrow, and spleen. CONCLUSIONS Our data indicate that under basal laboratory conditions the lack of GPI-linked protein does not cause a retention of progenitor cells in the bone marrow. This implies that the preferential circulation of normal progenitor cells in patients with PNH requires an additional component that most likely is provided by the altered microenvironment of the underlying bone marrow failure.

  • effect of proinflammatory cytokines on PIGA hematopoiesis
    Experimental Hematology, 2003
    Co-Authors: Shashikant Kulkarni, Monica Bessler
    Abstract:

    Abstract Objective . Blood cells from patients with paroxysmal nocturnal hemoglobinuria lack glycosyl phosphatidylinositol (GPI)-linked proteins, due to a somatic mutation in the X-linked PIGA gene. It is believed that clonal expansion of PIGA − blood cells is due to a survival advantage in the hostile marrow environment of aplastic anemia. Here we investigated the effects of inhibitory cytokines in mice genetically engineered to have blood cells deficient in GPI-linked proteins. Materials and Methods . The effect of inhibitory cytokines (tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], macrophage inflammatory protein-1 alpha [MIP-1α], and transforming growth factor-β 1 [TGF-β 1 ]) was investigated, using clonogenic assays, competitive repopulation, and in vivo induction of proinflammatory cytokines by double-stranded RNA. The expression of Fas on progenitor cells and its up-regulation by inhibitory cytokines were analyzed by flow cytometry. Results . TNF-α, IFN-γ, MIP-1α, and TGF-β 1 suppressed colony formation in a dose-dependent fashion that was similar for PIGA + and PIGA − blood bone marrow cells. Competitive repopulation of bone marrow cells cultured in IFN-γ and TNF-α resulted in a comparable ability of PIGA + and PIGA − hematopoietic stem cells to reconstitute hematopoiesis. Fas expression was minimal on PIGA + and PIGA − progenitor cells and was up-regulated to the same extent in response to IFN-γ and TNF-α as assessed by Fas antibody-mediated apoptosis. Similarly, in vivo induction of proinflammatory cytokines by double-stranded RNA had no effect on the proportion of circulating PIGA − blood cells. Conclusions . These results indicate that PIGA + and PIGA − hematopoietic progenitor cells respond similarly to inhibitory cytokines, suggesting that other factors are responsible for the clonal expansion of paroxysmal nocturnal hemoglobinuria cells.

  • high dose cyclophosphamide does not eradicate paroxysmal nocturnal haemoglobinuria haematopoiesis in mice carrying a PIGA gene mutation
    British Journal of Haematology, 2003
    Co-Authors: Anne Schaefer, Marek Jasinski, Monica Bessler
    Abstract:

    Recently, high-dose cyclophosphamide (HD CY) has been used in the treatment of aplastic anaemia. Several reports have suggested that the treatment may either eradicate or suppress mutant clonal haematopoiesis such as paroxysmal nocturnal haemoglobinuria (PNH). We therefore treated mice that have a proportion of blood cells deficient in GPI-anchor molecules (PIGA-) with HD CY, and monitored their peripheral blood counts during and after treatment. HD CY produced a transient myelosuppression; however, the contribution of PIGA- haematopoiesis to the peripheral blood remained unchanged, suggesting that HD CY is unlikely to eliminate an existing PNH clone in patients treated for aplastic anaemia.

  • the effect of gpi anchor deficiency on apoptosis in mice carrying a PIGA gene mutation in hematopoietic cells
    Journal of Leukocyte Biology, 2002
    Co-Authors: Shashikant Kulkarni, Monica Bessler
    Abstract:

    Glycosyl phosphatidylinositol (GPI) an- chors are used by a variety of proteins to link to the cell surface. GPI-anchored proteins are deficient on a proportion of blood cells from patients with paroxysmal nocturnal hemoglobinuria. This is caused by the expansion of a cell clone that has acquired a mutation in a gene, PIGA, which is essential in the synthesis of GPI anchors. The na- ture of the growth/survival advantage permitting the expansion of PIGA - cells is unknown. A de- creased susceptibility to apoptosis has been found in blood cells from patients, but the contribution of the PIGA gene mutation to this finding remained controversial. Therefore, we investigated apopto- sis in mice that harbor a targeted PIGA gene muta- tion in hematopoietic cells. When exposed to a variety of apoptotic stimuli, apoptosis in PIGA - thymocytes, granulocytes, and hematopoietic pro- genitor cells was similar to apoptosis induced in PIGA cells from the same mouse or from wild- type controls. Similarly, whole-body -irradiation did not produce an in vivo survival advantage of PIGA - hematopoietic stem cells. Our findings imply that a PIGA gene mutation does not alter suscepti- bility to cell death, indicating that other factors in addition to the PIGA gene mutation are necessary to promote the clonal outgrowth of PIGA - cells. J. Leukoc. Biol. 72: 1228-1233; 2002.

Silke Pauli - One of the best experts on this subject based on the ideXlab platform.

  • a novel mutation in PIGA associated with multiple congenital anomalies hypotonia seizure syndrome 2 mcahs2 in a boy with a combination of severe epilepsy and gingival hyperplasia
    Molecular Syndromology, 2020
    Co-Authors: Christiane Neuhofer, Rudolf Funke, Bernd Wilken, Alexej Knaus, Janine Altmuller, Peter Nurnberg, Bernd Wollnik, Peter Burfeind, Silke Pauli
    Abstract:

    Multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) is a rare disease caused by mutations in the X chromosomal PIGA gene. Clinically it is characterized by early-onset epilepsy, hypotonia, dysmorphic features, and variable congenital anomalies. PIGA codes for the phosphatidylinositol glycan-class A protein, which forms a subunit of an enzymatic complex involved in glycophosphatidylinositol (GPI) biosynthesis. We present a new case of MCAHS2 and perform a comprehensive review of the available literature to delineate the phenotypical traits associated with germline PIGA mutations. Furthermore, we provide functional evidence of pathogenicity of the novel missense mutation, c.154C>T; (p.His52Tyr), in the PIGA gene causative of MCAHS2 in our patient. By flow cytometry, we observed reduced expression of GPI-anchored surface proteins in patient granulocytes compared to control samples, proving GPI-biogenesis impairment. The patient's severe epilepsy with several daily attacks was refractory to treatment, but the frequency of seizures reduced temporarily under triple therapy with perampanel, rufinamide and vigabatrin. Our study delineates the known MCAHS2 phenotype and discusses challenges of diagnosis and clinical management in this complex, rare disease. Furthermore, we present a novel mutation with functional evidence of pathogenicity.

Kathryn J Swoboda - One of the best experts on this subject based on the ideXlab platform.

  • a novel germline PIGA mutation in ferro cerebro cutaneous syndrome a neurodegenerative x linked epileptic encephalopathy with systemic iron overload
    American Journal of Medical Genetics Part A, 2014
    Co-Authors: Kathryn J Swoboda, Rebecca L Margraf, John C Carey, Holly Zhou, Tara M Newcomb, Emily M Coonrod, Jacob D Durtschi, Kalyan Mallempati, Attila Kumanovics
    Abstract:

    Three related males presented with a newly recognized x-linked syndrome associated with neurodegeneration, cutaneous abnormalities, and systemic iron overload. Linkage studies demonstrated that they shared a haplotype on Xp21.3-Xp22.2 and exome sequencing was used to identify candidate variants. Of the segregating variants, only a PIGA mutation segregated with disease in the family. The c.328_330delCCT PIGA variant predicts, p.Leu110del (or c.1030_1032delCTT, p.Leu344del depending on the reference sequence). The unaffected great-grandfather shared his X allele with the proband but he did not have the PIGA mutation, indicating that the mutation arose de novo in his daughter. A single family with a germline PIGA mutation has been reported; affected males had a phenotype characterized by multiple congenital anomalies and severe neurologic impairment resulting in infantile lethality. In contrast, affected boys in the family described here were born without anomalies and were neurologically normal prior to onset of seizures after 6 months of age, with two surviving to the second decade. PIGA encodes an enzyme in the GPI anchor biosynthesis pathway. An affected individual in the family studied here was deficient in GPI anchor proteins on granulocytes but not erythrocytes. In conclusion, the PIGA mutation in this family likely causes a reduction in GPI anchor protein cell surface expression in various cell types, resulting in the observed pleiotropic phenotype involving central nervous system, skin, and iron metabolism.

  • a novel germline PIGA mutation in ferro cerebro cutaneous syndrome a neurodegenerative x linked epileptic encephalopathy with systemic iron overload
    American Journal of Medical Genetics Part A, 2014
    Co-Authors: Kathryn J Swoboda, Rebecca L Margraf, John C Carey, Holly Zhou, Tara M Newcomb, Emily M Coonrod, Jacob D Durtschi, Kalyan Mallempati, Attila Kumanovics
    Abstract:

    Three related males presented with a newly recognized x-linked syndrome associated with neurodegeneration, cutaneous abnormalities, and systemic iron overload. Linkage studies demonstrated that they shared a haplotype on Xp21.3–Xp22.2 and exome sequencing was used to identify candidate variants. Of the segregating variants, only a PIGA mutation segregated with disease in the family. The c.328_330delCCT PIGA variant predicts, p.Leu110del (or c.1030_1032delCTT, p.Leu344del depending on the reference sequence). The unaffected great-grandfather shared his X allele with the proband but he did not have the PIGA mutation, indicating that the mutation arose de novo in his daughter. A single family with a germline PIGA mutation has been reported; affected males had a phenotype characterized by multiple congenital anomalies and severe neurologic impairment resulting in infantile lethality. In contrast, affected boys in the family described here were born without anomalies and were neurologically normal prior to onset of seizures after 6 months of age, with two surviving to the second decade. PIGA encodes an enzyme in the GPI anchor biosynthesis pathway. An affected individual in the family studied here was deficient in GPI anchor proteins on granulocytes but not erythrocytes. In conclusion, the PIGA mutation in this family likely causes a reduction in GPI anchor protein cell surface expression in various cell types, resulting in the observed pleiotropic phenotype involving central nervous system, skin, and iron metabolism. © 2013 Wiley Periodicals, Inc.

Robert A Brodsky - One of the best experts on this subject based on the ideXlab platform.

  • a hypomorphic PIGA gene mutation causes severe defects in neuron development and susceptibility to complement mediated toxicity in a human ipsc model
    PLOS ONE, 2017
    Co-Authors: Xuan Yuan, Linzhao Cheng, Leslie G Biesecker, Andrea C Baines, Eleni Gavriilaki, Zhexing Wen, Evan M Braunstein, Xinzhong Dong, Robert A Brodsky
    Abstract:

    Mutations in genes involved in glycosylphosphatidylinositol (GPI) anchor biosynthesis underlie a group of congenital syndromes characterized by severe neurodevelopmental defects. GPI anchored proteins have diverse roles in cell adhesion, signaling, metabolism and complement regulation. Over 30 enzymes are required for GPI anchor biosynthesis and PIGA is involved in the first step of this process. A hypomorphic mutation in the X-linked PIGA gene (c.1234C>T) causes multiple congenital anomalies hypotonia seizure syndrome 2 (MCAHS2), indicating that even partial reduction of GPI anchored proteins dramatically impairs central nervous system development, but the mechanism is unclear. Here, we established a human induced pluripotent stem cell (hiPSC) model containing the PIGAc.1234C>T mutation to study the effects of a hypomorphic allele of PIGA on neuronal development. Neuronal differentiation from neural progenitor cells generated by EB formation in PIGAc.1234C>T is significantly impaired with decreased proliferation, aberrant synapse formation and abnormal membrane depolarization. The results provide direct evidence for a critical role of GPI anchor proteins in early neurodevelopment. Furthermore, neural progenitors derived from PIGAc.1234C>T hiPSCs demonstrate increased susceptibility to complement-mediated cytotoxicity, suggesting that defective complement regulation may contribute to neurodevelopmental disorders.

  • early frameshift mutation in PIGA identified in a large xlid family without neonatal lethality
    Human Mutation, 2014
    Co-Authors: Stefanie Belet, Nathalie Fieremans, Xuan Yuan, Hilde Van Esch, Jelle Verbeeck, Linzhao Cheng, Brett R Brodsky, Vera M Kalscheuer, Robert A Brodsky, Guy Froyen
    Abstract:

    The phosphatidylinositol glycan class A (PIGA) protein is a member of the glycosylphosphatidylinositol anchor pathway. Germline mutations in PIGA located at Xp22.2 are thought to be lethal in males. However, a nonsense mutation in the last coding exon was recently described in two brothers with multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) who survived through birth likely because of the hypomorphic nature of the truncated protein, but died in their first weeks of life. Here, we report on a frameshift mutation early in the PIGA cDNA (c.76dupT; p.Y26Lfs*3) that cosegregates with the disease in a large family diagnosed with a severe syndromic form of X-linked intellectual disability. Unexpectedly, CD59 surface expression suggested the production of a shorter PIGA protein with residual functionality. We provide evidence that the second methionine at position 37 may be used for the translation of a 36 amino acids shorter PIGA. Complementation assays confirmed that this shorter PIGA cDNA was able to partially rescue the surface expression of CD59 in a PIGA-null cell line. Taken together, our data strongly suggest that the early frameshift mutation in PIGA produces a truncated hypomorph, which is sufficient to rescue the lethality in males but not the MCAHS2-like phenotype.

  • the phenotype of a germline mutation in PIGA the gene somatically mutated in paroxysmal nocturnal hemoglobinuria
    American Journal of Human Genetics, 2012
    Co-Authors: Jennifer J Johnston, Xuan Yuan, Linzhao Cheng, Robert A Brodsky, Andrea L Gropman, Julie C Sapp, Jamie K Teer, Jodie M Martin, Cyndi F Liu, Leslie G Biesecker
    Abstract:

    Phosphatidylinositol glycan class A (PIGA) is involved in the first step of glycosylphosphatidylinositol (GPI) biosynthesis. Many proteins, including CD55 and CD59, are anchored to the cell by GPI. Loss of CD55 and CD59 on erythrocytes causes complement-mediated lysis in paroxysmal nocturnal hemoglobinuria (PNH), a disease that manifests after clonal expansion of hematopoietic cells with somatic PIGA mutations. Although somatic PIGA mutations have been identified in many PNH patients, it has been proposed that germline mutations are lethal. We report a family with an X-linked lethal disorder involving cleft palate, neonatal seizures, contractures, central nervous system (CNS) structural malformations, and other anomalies. An X chromosome exome next-generation sequencing screen identified a single nonsense PIGA mutation, c.1234C>T, which predicts p.Arg412∗. This variant segregated with disease and carrier status in the family, is similar to mutations known to cause PNH as a result of PIGA dysfunction, and was absent in 409 controls. PIGA-null mutations are thought to be embryonic lethal, suggesting that p.Arg412∗ PIGA has residual function. Transfection of a mutant p.Arg412∗ PIGA construct into PIGA-null cells showed partial restoration of GPI-anchored proteins. The genetic data show that the c.1234C>T (p.Arg412∗) mutation is present in an affected child, is linked to the affected chromosome in this family, is rare in the population, and results in reduced, but not absent, biosynthesis of GPI anchors. We conclude that c.1234C>T in PIGA results in the lethal X-linked phenotype recognized in the reported family.