The Experts below are selected from a list of 372 Experts worldwide ranked by ideXlab platform
Michael Cantz - One of the best experts on this subject based on the ideXlab platform.
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identification of a ctl4 neu1 fusion transcript in a Sialidosis patient
FEBS Letters, 2002Co-Authors: Roland Penzel, Consolato Sergi, Jurgen Kopitz, H F Otto, Michael CantzAbstract:The deficiency of the lysosomal neuraminidase (NEU1; sialidase) causes the storage disorder Sialidosis with symptoms ranging from eye abnormalities and neurological disturbances to skeletal malformations, mental retardation and early death. Sialidosis patients encompassing a wide spectrum of clinical symptoms were screened for mutations in neu1. We identified the same homozygous interstitial deletion (11 kb) in two patients causing the fusion of exon 10 of CTL4 (New Gene 22; NG22) with the 3′-UTR of neu1. In one patient we found the resulting CTL4/Neu1 fusion transcript, in the other we detected an alternatively spliced CTL4 transcript (retention of intron 9).
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Identification of a CTL4/Neu1 fusion transcript in a Sialidosis patient.
FEBS letters, 2002Co-Authors: Roland Penzel, Consolato Sergi, Jurgen Kopitz, H F Otto, Michael CantzAbstract:The deficiency of the lysosomal neuraminidase (NEU1; sialidase) causes the storage disorder Sialidosis with symptoms ranging from eye abnormalities and neurological disturbances to skeletal malformations, mental retardation and early death. Sialidosis patients encompassing a wide spectrum of clinical symptoms were screened for mutations in neu1. We identified the same homozygous interstitial deletion (11 kb) in two patients causing the fusion of exon 10 of CTL4 (New Gene 22; NG22) with the 3'-UTR of neu1. In one patient we found the resulting CTL4/Neu1 fusion transcript, in the other we detected an alternatively spliced CTL4 transcript (retention of intron 9).
Alessandra Dazzo - One of the best experts on this subject based on the ideXlab platform.
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intermittent enzyme replacement therapy with recombinant human β galactosidase prevents neuraminidase 1 deficiency
Journal of Biological Chemistry, 2020Co-Authors: Amanda R Luu, Alessandra Dazzo, Cara Wong, Vishal Agrawal, Nathan Wise, Britta Handyside, Glenn Pacheco, Jessica B Felix, Alexander Giaramita, Jon VinceletteAbstract:Mutations in the galactosidase β 1 (GLB1) gene cause lysosomal β-galactosidase (β-Gal) deficiency and clinical onset of the neurodegenerative lysosomal storage disease, GM1 gangliosidosis. β-Gal and neuraminidase 1 (NEU1) form a multienzyme complex in lysosomes along with the molecular chaperone, protective protein cathepsin A (PPCA). NEU1 is deficient in the neurodegenerative lysosomal storage disease Sialidosis, and its targeting to and stability in lysosomes strictly depend on PPCA. In contrast, β-Gal only partially depends on PPCA, prompting us to investigate the role that β-Gal plays in the multienzyme complex. Here, we demonstrate that β-Gal negatively regulates NEU1 levels in lysosomes by competitively displacing this labile sialidase from PPCA. Chronic cellular uptake of purified recombinant human β-Gal (rhβ-Gal) or chronic lentiviral-mediated GLB1 overexpression in GM1 gangliosidosis patient fibroblasts coincides with profound secondary NEU1 deficiency. A regimen of intermittent enzyme replacement therapy dosing with rhβ-Gal, followed by enzyme withdrawal, is sufficient to augment β-Gal activity levels in GM1 gangliosidosis patient fibroblasts without promoting NEU1 deficiency. In the absence of β-Gal, NEU1 levels are elevated in the GM1 gangliosidosis mouse brain, which are restored to normal levels following weekly intracerebroventricular dosing with rhβ-Gal. Collectively, our results highlight the need to carefully titrate the dose and dosing frequency of β-Gal augmentation therapy for GM1 gangliosidosis. They further suggest that intermittent intracerebroventricular enzyme replacement therapy dosing with rhβ-Gal is a tunable approach that can safely augment β-Gal levels while maintaining NEU1 at physiological levels in the GM1 gangliosidosis brain.
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in silico identification of new putative pathogenic variants in the neu1 sialidase gene affecting enzyme function and subcellular localization
PLOS ONE, 2014Co-Authors: Dario Bonardi, Alessandra Dazzo, Viola Ravasio, Giuseppe Borsani, Roberto Bresciani, Eugenio Monti, Edoardo GiacopuzziAbstract:The NEU1 gene is the first identified member of the human sialidases, glycohydrolitic enzymes that remove the terminal sialic acid from oligosaccharide chains. Mutations in NEU1 gene are causative of Sialidosis (MIM 256550), a severe lysosomal storage disorder showing autosomal recessive mode of inheritance. Sialidosis has been classified into two subtypes: Sialidosis type I, a normomorphic, late-onset form, and Sialidosis type II, a more severe neonatal or early-onset form. A total of 50 causative mutations are reported in HGMD database, most of which are missense variants. To further characterize the NEU1 gene and identify new functionally relevant protein isoforms, we decided to study its genetic variability in the human population using the data generated by two large sequencing projects: the 1000 Genomes Project (1000G) and the NHLBI GO Exome Sequencing Project (ESP). Together these two datasets comprise a cohort of 7595 sequenced individuals, making it possible to identify rare variants and dissect population specific ones. By integrating this approach with biochemical and cellular studies, we were able to identify new rare missense and frameshift alleles in NEU1 gene. Among the 9 candidate variants tested, only two resulted in significantly lower levels of sialidase activity (p C and c.700G>A. These two mutations give rise to the amino acid substitutions p.V217A and p.D234N, respectively. NEU1 variants including either of these two amino acid changes have 44% and 25% residual sialidase activity when compared to the wild-type enzyme, reduced protein levels and altered subcellular localization. Thus they may represent new, putative pathological mutations resulting in Sialidosis type I. The in silico approach used in this study has enabled the identification of previously unknown NEU1 functional alleles that are widespread in the population and could be tested in future functional studies.
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type ii Sialidosis review of the clinical spectrum and identification of a new splicing defect with chitotriosidase assessment in two patients
Journal of Neurology, 2009Co-Authors: Anna Caciotti, M Di Rocco, Mirella Filocamo, Serena Grossi, F Traverso, Catia Cavicchi, A Messeri, Renzo Guerrini, Alessandra Dazzo, Enrico ZammarchiAbstract:Sialidosis is a lysosomal storage disease caused by the deficiency of alpha-N-acetyl neuraminidase-1 (NEU1). Sialidosis is classified into two main clinical variants: Type I, the milder form of the disease, and Type II, which can in turn be subdivided into three forms: congenital, infantile and juvenile. We report herein the clinical, biochemical and molecular characterisation of two patients with Type II Sialidosis exhibiting the congenital (P1) and infantile forms (P2). We also review clinical data on the rare Type II forms of Sialidosis in the hope of improving understanding of the disorder and facilitating its diagnosis. The genetic characterization of the two patients showed one known [c. 679G > A (p.G227R)] NEU1 missense mutation (detected in P2), and the new c.807 + 1G > A splicing defect (detected in P1), a genetic lesion that is extremely rare in this disease. Interestingly, P2 presented an extremely elevated level of chitotriosidase in plasma. This is the first pathological detection of chitotriosidase in Sialidosis patients.
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systemic and neurologic abnormalities distinguish the lysosomal disorders Sialidosis and galactoSialidosis in mice
Human Molecular Genetics, 2002Co-Authors: Natalie De Geest, Erik Bonten, Linda Mann, Jean De Sousahitzler, Christopher N Hahn, Alessandra DazzoAbstract:Neuraminidase initiates the hydrolysis of sialo-glycoconjugates by removing their terminal sialic acid residues. In humans, primary or secondary deficiency of this enzyme leads to two clinically similar neurodegenerative lysosomal storage disorders: Sialidosis and galactoSialidosis (GS). Mice nullizygous at the Neu1 locus develop clinical abnormalities reminiscent of early-onset Sialidosis in children, including severe nephropathy, progressive edema, splenomegaly, kyphosis and urinary excretion of sialylated oligosaccharides. Although the Sialidosis mouse model shares clinical and histopathological features with GS mice and GS patients, we have identified phenotypic abnormalities that seem specific for Sialidosis mice. These include progressive deformity of the spine, high incidence of premature death, age-related extramedullary hematopoiesis, and lack of early degeneration of cerebellar Purkinje cells. The differences and similarities identified in these Sialidosis and GS mice may help to better understand the pathophysiology of these diseases in children and to identify more targeted therapies for each of these diseases.
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a point mutation in the neu 1 locus causes the neuraminidase defect in the sm j mouse
Human Molecular Genetics, 1998Co-Authors: Robbert J Rottier, Erik Bonten, Alessandra DazzoAbstract:Lysosomal neuraminidase (sialidase) occurs in a high molecular weight complex with the glycosidase beta-galactosidase and the serine carboxypeptidase protective protein/cathepsin A (PPCA). Association of the enzyme with PPCA is crucial for its correct targeting and lysosomal activation. In man two genetically distinct storage disorders are associated with either a primary or a secondary deficiency of lysosomal neuraminidase: Sialidosis and galactoSialidosis. In the mouse the naturally occurring inbred strain SM/J presents with a number of phenotypic abnormalities that have been attributed to reduced neuraminidase activity. SM/J mice were originally characterized by their altered sialylation of several lysosomal glycoproteins. This defect was linked to a single gene, neu-1 , on chromosome 17, which was mapped by linkage analysis to the H-2 locus. In addition, these mice have an altered immune response that has also been coupled to a deficiency of the Neu-1 neuraminidase. Here we report the identification in SM/J mice of a single amino acid substitution (L209I) in the Neu-1 protein which is responsible for the partial deficiency of lysosomal neuraminidase. We propose that the reduced activity is caused by the enzyme's altered affinity for its substrate, rather than a change in substrate specificity or turnover rate. The mutant enzyme is correctly compartmentalized in lysosomes and maintains the ability to associate with its activating protein, PPCA. We propose that it is this mutation that is responsible for the SM/J phenotype.
John W. Callahan - One of the best experts on this subject based on the ideXlab platform.
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molecular basis of gm1 gangliosidosis and morquio disease type b structure function studies of lysosomal beta galactosidase and the non lysosomal beta galactosidase like protein
Biochimica et Biophysica Acta, 1999Co-Authors: John W. CallahanAbstract:GM1 gangliosidosis and Morquio B disease are distinct disorders both clinically and biochemically yet they arise from the same beta-galactosidase enzyme deficiency. On the other hand, galactoSialidosis and Sialidosis share common clinical and biochemical features, yet they arise from two separate enzyme deficiencies, namely, protective protein/cathepsin A and neuraminidase, respectively. However distinct, in practice these disorders overlap both clinically and biochemically so that easy discrimination between them is sometimes difficult. The principle reason for this may be found in the fact that these three enzymes form a unique complex in lysosomes that is required for their stability and posttranslational processing. In this review, I focus mainly on the primary and secondary beta-galactosidase deficiency states and offer some hypotheses to account for differences between GM1 gangliosidosis and Morquio B disease.
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molecular basis of gm1 gangliosidosis and morquio disease type b structure function studies of lysosomal beta galactosidase and the non lysosomal beta galactosidase like protein
Biochimica et Biophysica Acta, 1999Co-Authors: John W. CallahanAbstract:Abstract GM1 gangliosidosis and Morquio B disease are distinct disorders both clinically and biochemically yet they arise from the same β-galactosidase enzyme deficiency. On the other hand, galactoSialidosis and Sialidosis share common clinical and biochemical features, yet they arise from two separate enzyme deficiencies, namely, protective protein/cathepsin A and neuraminidase, respectively. However distinct, in practice these disorders overlap both clinically and biochemically so that easy discrimination between them is sometimes difficult. The principle reason for this may be found in the fact that these three enzymes form a unique complex in lysosomes that is required for their stability and posttranslational processing. In this review, I focus mainly on the primary and secondary β-galactosidase deficiency states and offer some hypotheses to account for differences between GM1 gangliosidosis and Morquio B disease.
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molecular basis of gm1 gangliosidosis and morquio disease type b structure function studies of lysosomal β galactosidase and the non lysosomal β galactosidase like protein
Biochimica et Biophysica Acta, 1999Co-Authors: John W. CallahanAbstract:Abstract GM1 gangliosidosis and Morquio B disease are distinct disorders both clinically and biochemically yet they arise from the same β-galactosidase enzyme deficiency. On the other hand, galactoSialidosis and Sialidosis share common clinical and biochemical features, yet they arise from two separate enzyme deficiencies, namely, protective protein/cathepsin A and neuraminidase, respectively. However distinct, in practice these disorders overlap both clinically and biochemically so that easy discrimination between them is sometimes difficult. The principle reason for this may be found in the fact that these three enzymes form a unique complex in lysosomes that is required for their stability and posttranslational processing. In this review, I focus mainly on the primary and secondary β-galactosidase deficiency states and offer some hypotheses to account for differences between GM1 gangliosidosis and Morquio B disease.
Roland Penzel - One of the best experts on this subject based on the ideXlab platform.
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identification of a ctl4 neu1 fusion transcript in a Sialidosis patient
FEBS Letters, 2002Co-Authors: Roland Penzel, Consolato Sergi, Jurgen Kopitz, H F Otto, Michael CantzAbstract:The deficiency of the lysosomal neuraminidase (NEU1; sialidase) causes the storage disorder Sialidosis with symptoms ranging from eye abnormalities and neurological disturbances to skeletal malformations, mental retardation and early death. Sialidosis patients encompassing a wide spectrum of clinical symptoms were screened for mutations in neu1. We identified the same homozygous interstitial deletion (11 kb) in two patients causing the fusion of exon 10 of CTL4 (New Gene 22; NG22) with the 3′-UTR of neu1. In one patient we found the resulting CTL4/Neu1 fusion transcript, in the other we detected an alternatively spliced CTL4 transcript (retention of intron 9).
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Identification of a CTL4/Neu1 fusion transcript in a Sialidosis patient.
FEBS letters, 2002Co-Authors: Roland Penzel, Consolato Sergi, Jurgen Kopitz, H F Otto, Michael CantzAbstract:The deficiency of the lysosomal neuraminidase (NEU1; sialidase) causes the storage disorder Sialidosis with symptoms ranging from eye abnormalities and neurological disturbances to skeletal malformations, mental retardation and early death. Sialidosis patients encompassing a wide spectrum of clinical symptoms were screened for mutations in neu1. We identified the same homozygous interstitial deletion (11 kb) in two patients causing the fusion of exon 10 of CTL4 (New Gene 22; NG22) with the 3'-UTR of neu1. In one patient we found the resulting CTL4/Neu1 fusion transcript, in the other we detected an alternatively spliced CTL4 transcript (retention of intron 9).
Erik Bonten - One of the best experts on this subject based on the ideXlab platform.
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Vacuolization and alterations of lysosomal membrane proteins in cochlear marginal cells contribute to hearing loss in neuraminidase 1-deficient mice
Biochimica et Biophysica Acta, 2009Co-Authors: Xudong Wu, Erik Bonten, Huimin Hu, Katherine A. Steigelman, Wenxuan He, Alessandra D'azzoAbstract:Abstract The neuraminidase-1 ( Neu1 ) knockout mouse model is a phenocopy of the lysosomal storage disease (LSD) Sialidosis, characterized by multisystemic and neuropathic symptoms, including hearing loss. We have characterized the auditory defects in Neu1 − / − mice and found that hearing loss involves both conductive and sensorineural components. Auditory brainstem response (ABR) thresholds were significantly elevated in Neu1 − / − mice at P21 (48 –55 dB), and hearing loss appeared progressive (53 –66 dB at P60). At these ages Neu1 − / − mice accumulated cerumen in the external ear canal and had a thickened mucosa and inflammation in the middle ear. In cochleae of adult wild-type mice, Neu1 was expressed in several cell types in the stria vascularis, the organ of Corti, and spiral ganglion. Progressive morphological abnormalities such as extensive vacuolization were detected in the Neu1 − / − cochleae as early as P9. These early morphologic changes in Neu1 − / − cochleae were associated with oversialylation of several lysosomal associated membrane proteins (Lamps) in the stria vascularis. A marked increase in the expression and apical localization of Lamp-1 in marginal cells of the stria vascularis predicts exacerbation of lysosomal exocytosis into the endolymph. Consequently, the endolymphatic potential in Neu1 − / − mice was reduced by approximately 20 mV at ages P31–P44, which would cause dysfunction of transduction in sensory hair cells. This study suggests a molecular mechanism that contributes to hearing loss in Sialidosis and identifies potential therapeutic targets.
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Neuraminidase 1 is a negative regulator of lysosomal exocytosis.
Developmental Cell, 2008Co-Authors: Gouri Yogalingam, Diantha Van De Vlekkert, Simon Moshiach, Samuel Connell, Erik Bonten, Huimin Hu, Alessandra D'azzoAbstract:Summary Lysosomal exocytosis is a Ca 2+ -regulated mechanism that involves proteins responsible for cytoskeletal attachment and fusion of lysosomes with the plasma membrane. However, whether luminal lysosomal enzymes contribute to this process remains unknown. Here we show that neuraminidase NEU1 negatively regulates lysosomal exocytosis in hematopoietic cells by processing the sialic acids on the lysosomal membrane protein LAMP-1. In macrophages from NEU1-deficient mice, a model of the disease Sialidosis, and in patients' fibroblasts, oversialylated LAMP-1 enhances lysosomal exocytosis. Silencing of LAMP-1 reverts this phenotype by interfering with the docking of lysosomes at the plasma membrane. In neu1 −/− mice the excessive exocytosis of serine proteases in the bone niche leads to inactivation of extracellular serpins, premature degradation of VCAM-1, and loss of bone marrow retention. Our findings uncover an unexpected mechanism influencing lysosomal exocytosis and argue that exacerbations of this process form the basis for certain genetic diseases.
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systemic and neurologic abnormalities distinguish the lysosomal disorders Sialidosis and galactoSialidosis in mice
Human Molecular Genetics, 2002Co-Authors: Natalie De Geest, Erik Bonten, Linda Mann, Jean De Sousahitzler, Christopher N Hahn, Alessandra DazzoAbstract:Neuraminidase initiates the hydrolysis of sialo-glycoconjugates by removing their terminal sialic acid residues. In humans, primary or secondary deficiency of this enzyme leads to two clinically similar neurodegenerative lysosomal storage disorders: Sialidosis and galactoSialidosis (GS). Mice nullizygous at the Neu1 locus develop clinical abnormalities reminiscent of early-onset Sialidosis in children, including severe nephropathy, progressive edema, splenomegaly, kyphosis and urinary excretion of sialylated oligosaccharides. Although the Sialidosis mouse model shares clinical and histopathological features with GS mice and GS patients, we have identified phenotypic abnormalities that seem specific for Sialidosis mice. These include progressive deformity of the spine, high incidence of premature death, age-related extramedullary hematopoiesis, and lack of early degeneration of cerebellar Purkinje cells. The differences and similarities identified in these Sialidosis and GS mice may help to better understand the pathophysiology of these diseases in children and to identify more targeted therapies for each of these diseases.
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a point mutation in the neu 1 locus causes the neuraminidase defect in the sm j mouse
Human Molecular Genetics, 1998Co-Authors: Robbert J Rottier, Erik Bonten, Alessandra DazzoAbstract:Lysosomal neuraminidase (sialidase) occurs in a high molecular weight complex with the glycosidase beta-galactosidase and the serine carboxypeptidase protective protein/cathepsin A (PPCA). Association of the enzyme with PPCA is crucial for its correct targeting and lysosomal activation. In man two genetically distinct storage disorders are associated with either a primary or a secondary deficiency of lysosomal neuraminidase: Sialidosis and galactoSialidosis. In the mouse the naturally occurring inbred strain SM/J presents with a number of phenotypic abnormalities that have been attributed to reduced neuraminidase activity. SM/J mice were originally characterized by their altered sialylation of several lysosomal glycoproteins. This defect was linked to a single gene, neu-1 , on chromosome 17, which was mapped by linkage analysis to the H-2 locus. In addition, these mice have an altered immune response that has also been coupled to a deficiency of the Neu-1 neuraminidase. Here we report the identification in SM/J mice of a single amino acid substitution (L209I) in the Neu-1 protein which is responsible for the partial deficiency of lysosomal neuraminidase. We propose that the reduced activity is caused by the enzyme's altered affinity for its substrate, rather than a change in substrate specificity or turnover rate. The mutant enzyme is correctly compartmentalized in lysosomes and maintains the ability to associate with its activating protein, PPCA. We propose that it is this mutation that is responsible for the SM/J phenotype.
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d’Azzo, A point mutation in the neu-1 locus causes the neuraminidase defect
1998Co-Authors: Robbert J Rottier, Erik BontenAbstract:Lysosomal neuraminidase (sialidase) occurs in a high molecular weight complex with the glycosidase β-galactosidase and the serine carboxypeptidase protective protein/cathepsin A (PPCA). Association of the enzyme with PPCA is crucial for its correct targeting and lysosomal activation. In man two genetically distinct storage disorders are associated with either a primary or a secondary deficiency of lysosomal neuraminidase: Sialidosis and galactoSialidosis. In the mouse the naturally occurring inbred strain SM/J presents with a number of phenotypic abnormalities that have been attributed to reduced neuraminidase activity. SM/J mice were originally characterized by their altered sialylation of several lysosomal glycoproteins. This defect was linked to a single gene, neu-1, on chromosome 17, which was mapped by linkage analysis to the H-2 locus. In addition, these mice have an altered immune response that has also been coupled to a deficiency of the Neu-1 neuraminidase. Here we report the identification in SM/J mice of a single amino acid substitution (L209I) in the Neu-1 protein which is responsible for the partial deficiency of lysosomal neuraminidase. We propose that the reduced activity is caused by the enzyme’s altered affinity for its substrate, rather than a change in substrate specificity or turnover rate. The mutant enzyme is correctly compartmentalized in lysosomes and maintains the ability to associate with its activating protein, PPCA. We propose that it is this mutation that is responsible for the SM/J phenotype