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[PMID]: 29247835
[Au] Autor:Banning A; Schiff M; Tikkanen R
[Ad] Address:Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
[Ti] Title:Amlexanox provides a potential therapy for nonsense mutations in the lysosomal storage disorder Aspartylglucosaminuria.
[So] Source:Biochim Biophys Acta;1864(3):668-675, 2018 Mar.
[Is] ISSN:0006-3002
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by mutations in the gene for aspartylglucosaminidase (AGA). This enzyme participates in glycoprotein degradation in lysosomes. AGU results in progressive mental retardation, and no curative therapy is currently available. We have here characterized the consequences of AGA gene mutations in a compound heterozygous patient who exhibits a missense mutation producing a Ser72Pro substitution in one allele, and a nonsense mutation Trp168X in the other. Ser72 is not a catalytic residue, but is required for the stabilization of the active site conformation. Thus, Ser72Pro exchange impairs the autocatalytic activation of the AGA precursor, and results in a considerable reduction of the enzyme activity and in altered AGA precursor processing. Betaine, which can partially rescue the AGA activity in AGU patients carrying certain missense mutations, turned out to be ineffective in the case of Ser72Pro substitution. The Trp168X nonsense allele results in complete lack of AGA polypeptide due to nonsense-mediated decay (NMD) of the mRNA. Amlexanox, which inhibits NMD and causes a translational read-through, facilitated the synthesis of a full-length, functional AGA protein from the nonsense allele. This could be demonstrated as presence of the AGA polypeptide and increased enzyme activity upon Amlexanox treatment. Furthermore, in the Ser72Pro/Trp168X expressing cells, Amlexanox induced a synergistic increase in AGA activity and polypeptide processing due to enhanced processing of the Ser72Pro polypeptide. Our data show for the first time that Amlexanox might provide a valid therapy for AGU.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1712
[Cu] Class update date: 180207
[Lr] Last revision date:180207
[St] Status:In-Data-Review

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[PMID]: 28370531
[Au] Autor:Piraud M; Pettazzoni M; Menegaut L; Caillaud C; Nadjar Y; Vianey-Saban C; Froissart R
[Ad] Address:Service de Biochimie et Biologie Moléculaire Grand Est, UM Pathologies Métaboliques, Erythrocytaires et Dépistage Périnatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, France.
[Ti] Title:Development of a new tandem mass spectrometry method for urine and amniotic fluid screening of oligosaccharidoses.
[So] Source:Rapid Commun Mass Spectrom;31(11):951-963, 2017 Jun 15.
[Is] ISSN:1097-0231
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:RATIONALE: The first step in the diagnosis of oligosaccharidoses is to evidence abnormal oligosaccharides excreted in urine, usually performed by the poorly sensitive but efficient thin layer chromatography (TLC) method. Developing a tandem mass spectrometry (MS/MS) technique could be of great interest to replace TLC. METHODS: Abnormal underivatized oligosaccharides have been recently studied using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, allowing the unambiguous identification of oligosaccharidoses. Based on this previous work, we developed an advantageous and efficient liquid chromatography (LC)/MS/MS method using a more common triple quadrupole tandem mass spectrometer for oligosaccharides analysis. RESULTS: Oligosaccharidoses (n = 97) and control (n = 240) urine samples were analysed. A specific pattern was obtained for each oligosaccharidosis using this method. In urine, it allows not only the identification of all the oligosaccharidoses previously identified by TLC (fucosidosis, alphamannosidosis, aspartylglucosaminuria, GM1 gangliosidosis, sialidosis, galactosialidosis and Schindler disease), but also extends the field of diagnosis to mucolipidosis type II, Sandhoff disease, and ß-mannosidosis. The same technique was applied to 16 amniotic fluid supernatants from oligosaccharidosis-affected foetuses (n = 16) compared with 37 unaffected. All the affected foetuses could be clearly identified: sialidosis (n = 3), galactosialidosis (n = 4), aspartylglucosaminuria (n = 1), mucolipidosis type II (n = 4) or GM1 gangliosidosis (n = 4). This technique can be applied to early prenatal diagnosis as well as to the oligosaccharidosis screening in the case of non-immune hydrops fetalis. CONCLUSIONS: The method is quick and easy to run, with an LC analysis time of 13 min per sample. The quantitative validation could not be obtained in the absence of a specific standard and of a labelled internal standard for each compound. Even if this LC/MS/MS method is only qualitative, it is very specific and much more sensitive than TLC. It allows the urinary screening of oligosaccharidoses, even mild or late-onset forms, and the screening of antenatal forms in amniotic fluid. Copyright © 2017 John Wiley & Sons, Ltd.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1704
[Cu] Class update date: 170525
[Lr] Last revision date:170525
[St] Status:In-Data-Review
[do] DOI:10.1002/rcm.7860

  3 / 196 MEDLINE  
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[PMID]: 28346360
[Au] Autor:Banning A; König JF; Gray SJ; Tikkanen R
[Ad] Address:Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany. Antje.Banning@biochemie.med.uni-giessen.de.
[Ti] Title:Functional Analysis of the Ser149/Thr149 Variants of Human Aspartylglucosaminidase and Optimization of the Coding Sequence for Protein Production.
[So] Source:Int J Mol Sci;18(4), 2017 Mar 26.
[Is] ISSN:1422-0067
[Cp] Country of publication:Switzerland
[La] Language:eng
[Ab] Abstract:Aspartylglucosaminidase (AGA) is a lysosomal hydrolase that participates in the breakdown of glycoproteins. Defects in the AGA gene result in a lysosomal storage disorder, aspartylglucosaminuria (AGU), that manifests mainly as progressive mental retardation. A number of AGU missense mutations have been identified that result in reduced AGA activity. Human variants that contain either Ser or Thr in position 149 have been described, but it is unknown if this affects AGA processing or activity. Here, we have directly compared the Ser149/Thr149 variants of AGA and show that they do not differ in terms of relative specific activity or processing. Therefore, Thr149 AGA, which is the rare variant, can be considered as a neutral or benign variant. Furthermore, we have here produced codon-optimized versions of these two variants and show that they are expressed at significantly higher levels than AGA with the natural codon-usage. Since optimal AGA expression is of vital importance for both gene therapy and enzyme replacement, our data suggest that use of codon-optimized AGA may be beneficial for these therapy options.
[Mh] MeSH terms primary: Aspartylglucosylaminase/metabolism
[Mh] MeSH terms secundary: Aspartylglucosylaminase/chemistry
Aspartylglucosylaminase/genetics
Cells, Cultured
Fibroblasts/cytology
Fibroblasts/metabolism
Fibroblasts/pathology
Gene Frequency
Genotype
HEK293 Cells
HeLa Cells
Humans
Lysosomal Storage Diseases/enzymology
Lysosomal Storage Diseases/genetics
Lysosomal Storage Diseases/pathology
Lysosomes/chemistry
Lysosomes/metabolism
Plasmids/genetics
Plasmids/metabolism
Polymorphism, Single Nucleotide
Protein Subunits/chemistry
Protein Subunits/genetics
Protein Subunits/metabolism
Transfection
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Protein Subunits); EC 3.5.1.26 (Aspartylglucosylaminase)
[Em] Entry month:1704
[Cu] Class update date: 170507
[Lr] Last revision date:170507
[Js] Journal subset:IM
[Da] Date of entry for processing:170328
[St] Status:MEDLINE

  4 / 196 MEDLINE  
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[PMID]: 28341936
[Au] Autor:Tokola A; Brandstack N; Hakkarainen A; Salli E; Åberg L; Autti T
[Ad] Address:HUS Medical Imaging Center, Helsinki, Finland. anna.tokola@hus.fi.
[Ti] Title:Erratum to: White Matter Microstructure and Subcortical Gray Matter Structure Volumes in Aspartylglucosaminuria; a 5-Year Follow-up Brain MRI Study of an Adolescent with Aspartylglucosaminuria and His Healthy Twin Brother.
[So] Source:JIMD Rep;35:117, 2017.
[Is] ISSN:2192-8304
[Cp] Country of publication:Germany
[La] Language:eng
[Pt] Publication type:PUBLISHED ERRATUM
[Em] Entry month:1703
[Cu] Class update date: 171006
[Lr] Last revision date:171006
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.1007/8904_2017_18

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[PMID]: 28185224
[Au] Autor:Anna T; Nina B; Antti H; Eero S; Laura Å; Taina A
[Ad] Address:HUS Medical Imaging Center, Radiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. anna.tokola@hus.fi.
[Ti] Title:White Matter Microstructure and Subcortical Gray Matter Structure Volumes in Aspartylglucosaminuria; a 5-Year Follow-up Brain MRI Study of an Adolescent with Aspartylglucosaminuria and His Healthy Twin Brother.
[So] Source:JIMD Rep;35:105-115, 2017.
[Is] ISSN:2192-8304
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:OBJECTIVE: Aspartylglucosaminuria is an inherited, lysosomal storage disease causing progressive decline in cognitive and motor functions. The aim of this study was to evaluate volumes of subcortical gray matter structures and white matter microstructure in aspartylglucosaminuria in adolescence in a longitudinal study for the first time. METHODS: A boy with aspartylglucosaminuria and his healthy twin brother were imaged twice with a 3.0 T MRI scanner at the ages of 10 and 15 years. Subcortical gray matter structure volumes were measured using an atlas-based automatic method, and diffusion tensor imaging was used to evaluate the white matter microstructure of the corpus callosum and the thalamocortical pulvinar tracts. RESULTS: The subcortical gray matter structures were smaller at onset and diminished at follow-up in the affected twin, with the exception of the amygdala which was larger and remained the size. The largest difference in volume between the twins was found in the thalami. The total gray and white matter volumes decreased in the affected twin. In diffusion tensor imaging analysis, the fractional anisotropy was decreased at onset in the affected twin compared to the healthy brother in the evaluated tracts. The axial, radial and mean diffusivity values were increased in the affected twin. The difference between the twins increased slightly at follow-up. INTERPRETATION: The findings suggest that volumetric measurements and diffusion tensor imaging based microstructural analysis may be useful modalities for monitoring disease progression and response to emerging treatment in aspartylglucosaminuria, but further studies with more subjects are necessary to confirm the results.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1702
[Cu] Class update date: 171006
[Lr] Last revision date:171006
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.1007/8904_2016_36

  6 / 196 MEDLINE  
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[PMID]: 28063748
[Au] Autor:Yamamoto T; Shimojima K; Matsufuji M; Mashima R; Sakai E; Okuyama T
[Ad] Address:Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan; Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan. Electronic address: yamamoto.toshiyuki@twmu.ac.jp.
[Ti] Title:Aspartylglucosaminuria caused by a novel homozygous mutation in the AGA gene was identified by an exome-first approach in a patient from Japan.
[So] Source:Brain Dev;39(5):422-425, 2017 May.
[Is] ISSN:1872-7131
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:BACKGROUND: Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disorder caused by a deficiency of the lysosomal enzyme, aspartylglucosaminidase (AGA). This disorder is rare in the general population except in Finland. Since the most characteristic feature of this disorder is a progressive developmental regression, patients often show no specific symptoms in the initial stages, and thus early diagnosis is often challenging. CASE REPORT: We encountered a 16-year-old boy who began to show difficulties in his speech at the age of 6years. Due to a mild regression in his development, he gradually lost common daily abilities. His diagnosis was first obtained through exome sequencing that identified a novel homozygous mutation in the AGA gene. This result was reasonable because of parental consanguinity. Reduced enzymatic activity of AGA was then confirmed. His urine was retrospectively screened by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and a specific pattern of abnormal metabolites was identified. CONCLUSIONS: Because both exome sequencing and MALDI-TOF-MS screening are adaptable and comprehensive, future combinatory use of these methods would be useful for diagnosis of rare inborn errors of metabolism such as AGU.
[Mh] MeSH terms primary: Aspartylglucosaminuria/genetics
Aspartylglucosylaminase/genetics
Mutation/genetics
[Mh] MeSH terms secundary: Adolescent
Aspartylglucosaminuria/diagnostic imaging
Aspartylglucosylaminase/metabolism
Exome/genetics
Humans
Japan
Magnetic Resonance Imaging
Male
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Thalamus/diagnostic imaging
[Pt] Publication type:CASE REPORTS; JOURNAL ARTICLE
[Nm] Name of substance:EC 3.5.1.26 (Aspartylglucosylaminase)
[Em] Entry month:1704
[Cu] Class update date: 170417
[Lr] Last revision date:170417
[Js] Journal subset:IM
[Da] Date of entry for processing:170109
[St] Status:MEDLINE

  7 / 196 MEDLINE  
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[PMID]: 27469132
[Au] Autor:Ellsworth KA; Pollard LM; Cathey S; Wood T
[Ad] Address:Greenwood Genetic Center, 106 Gregor Mendel Circle, Greenwood, SC, 29646, USA.
[Ti] Title:Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs.
[So] Source:JIMD Rep;34:11-18, 2017.
[Is] ISSN:2192-8304
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:Keratan sulfate (KS) is commonly elevated in urine samples from patients with mucopolysaccharidosis type IVA (MPS IVA) and is considered pathognomonic for the condition. Recently, a new method has been described by Martell et al. to detect and measure urinary KS utilizing LC-MS/MS. As a part of the validation of this method in our laboratory, we studied the sensitivity and specificity of elevated urine KS levels using 25 samples from 15 MPS IVA patients, and 138 samples from 102 patients with other lysosomal storage disorders, including MPS I (n = 9), MPS II (n = 13), MPS III (n = 23), MPS VI (n = 7), beta-galactosidase deficiency (n = 7), mucolipidosis (ML) type II, II/III and III (n = 51), alpha-mannosidosis (n = 11), fucosidosis (n = 4), sialidosis (n = 5), Pompe disease (n = 3), aspartylglucosaminuria (n = 4), and galactosialidosis (n = 1). As expected, urine KS values were significantly higher (fivefold average increase) than age-matched controls in all MPS IVA patients. Urine KS levels were also significantly elevated (threefold to fourfold increase) in patients with GM-1 gangliosidosis, MPS IVB, ML II and ML II/III, and fucosidosis. Urine KS was also elevated to a smaller degree (1.1-fold to 1.7-fold average increase) in patients with MPS I, MPS II, and ML III. These findings suggest that while the UPLC-MS/MS urine KS method is 100% sensitive for the detection of patients with MPS IVA, elevated urine KS is not specific for this condition. Therefore, caution is advised when interpreting urinary keratan sulfate results.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1607
[Cu] Class update date: 170730
[Lr] Last revision date:170730
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.1007/8904_2016_1

  8 / 196 MEDLINE  
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[PMID]: 27906067
[Au] Autor:Arvio M; Mononen I
[Ad] Address:Päijät-Häme Social Welfare & Healthcare Joint Municipal Board, Lahti, Finland. maria.arvio@phsotey.fi.
[Ti] Title:Aspartylglycosaminuria: a review.
[So] Source:Orphanet J Rare Dis;11(1):162, 2016 12 01.
[Is] ISSN:1750-1172
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Aspartylglucosaminuria (AGU), a recessively inherited lysosomal storage disease, is the most common disorder of glycoprotein degradation with a high prevalence in the Finnish population. It is a lifelong condition affecting on the patient's appearance, cognition, adaptive skills, physical growth, personality, body structure, and health. An infantile growth spurt and development of macrocephalia associated to hernias and respiratory infections are the key signs to an early identification of AGU. Progressive intellectual and physical disability is the main symptom leading to death usually before the age of 50 years.The disease is caused by the deficient activity of the lysosomal enzyme glycosylasparaginase (aspartylglucosaminidase, AGA), which leads to a disorder in the degradation of glycoasparagines - aspartylglucosamine or other glycoconjugates with an aspartylglucosamine moiety at their reducing end - and accumulation of these undegraded glycoasparagines in tissues and body fluids. A single nucleotide change in the AGA gene resulting in a cysteine to serine substitution (C163S) in the AGA enzyme protein causes the deficiency of the glycosylasparaginase activity in the Finnish population. Homozygosity for the single nucleotide change causing the C163S mutation is responsible for 98% of the AGU cases in Finland simplifying the carrier detection and prenatal diagnosis of the disorder in the Finnish population. A mouse strain, which completely lacks the Aga activity has been generated through targeted disruption of the Aga gene in embryonic stem cells. These Aga-deficient mice share most of the clinical, histopathologic and biochemical characteristics of human AGU disease. Treatment of AGU mice with recombinant AGA resulted in rapid correction of the pathophysiologic characteristics of AGU in non-neuronal tissues of the animals. The accumulation of aspartylglucosamine was reduced by up to 40% in the brain tissue of the animals depending on the age of the animals and the therapeutic protocol. Enzyme replacement trials on human AGU patients have not been reported so far. Allogenic stem cell transplantation has not proved effective in curing AGU.
[Mh] MeSH terms primary: Aspartylglucosaminuria/metabolism
[Mh] MeSH terms secundary: Acetylglucosamine/analogs & derivatives
Acetylglucosamine/metabolism
Animals
Aspartylglucosaminuria/enzymology
Aspartylglucosaminuria/genetics
Aspartylglucosylaminase/genetics
Aspartylglucosylaminase/metabolism
Glycoproteins/metabolism
Humans
Lysosomal Storage Diseases/enzymology
Lysosomal Storage Diseases/genetics
Lysosomal Storage Diseases/metabolism
Mutation
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Nm] Name of substance:0 (Glycoproteins); 2776-93-4 (N-acetylglucosaminylasparagine); EC 3.5.1.26 (Aspartylglucosylaminase); V956696549 (Acetylglucosamine)
[Em] Entry month:1711
[Cu] Class update date: 171107
[Lr] Last revision date:171107
[Js] Journal subset:IM
[Da] Date of entry for processing:161202
[St] Status:MEDLINE

  9 / 196 MEDLINE  
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[PMID]: 27876883
[Au] Autor:Banning A; Gülec C; Rouvinen J; Gray SJ; Tikkanen R
[Ad] Address:Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
[Ti] Title:Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria.
[So] Source:Sci Rep;6:37583, 2016 Nov 23.
[Is] ISSN:2045-2322
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Aspartylglucosaminuria (AGU) is a lysosomal storage disorder that is caused by genetic deficiency of the enzyme aspartylglucosaminidase (AGA) which is involved in glycoprotein degradation. AGU is a progressive disorder that results in severe mental retardation in early adulthood. No curative therapy is currently available for AGU. We have here characterized the consequences of a novel AGU mutation that results in Thr122Lys exchange in AGA, and compared this mutant form to one carrying the worldwide most common AGU mutation, AGU-Fin. We show that T122K mutated AGA is expressed in normal amounts and localized in lysosomes, but exhibits low AGA activity due to impaired processing of the precursor molecule into subunits. Coexpression of T122K with wildtype AGA results in processing of the precursor into subunits, implicating that the mutation causes a local misfolding that prevents the precursor from becoming processed. Similar data were obtained for the AGU-Fin mutant polypeptide. We have here also identified small chemical compounds that function as chemical or pharmacological chaperones for the mutant AGA. Treatment of patient fibroblasts with these compounds results in increased AGA activity and processing, implicating that these substances may be suitable for chaperone mediated therapy for AGU.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1611
[Cu] Class update date: 170220
[Lr] Last revision date:170220
[St] Status:In-Data-Review
[do] DOI:10.1038/srep37583

  10 / 196 MEDLINE  
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[PMID]: 27549151
[Au] Autor:Kartal A; Aydin K
[Ad] Address:Department of Child Neurology, Faculty of Medicine, Selçuk University, Turkey kartalays@gmail.com.
[Ti] Title:Brain MRI findings in two Turkish pediatric patients with aspartylglucosaminuria.
[So] Source:Neuroradiol J;29(5):310-3, 2016 Oct.
[Is] ISSN:2385-1996
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Aspartylglucosaminuria is a rare lysosomal storage disorder that occurs as a result of a deficiency of the aspartylglucosaminidase enzyme. Because the disease is commonly referred to as the Finnish disease heritage, it is underdiagnosed outside of Finland. To date, only three Turkish patients are described in the literature. Here we describe the clinical and brain magnetic resonance imaging findings in two Turkish cousins with aspartylglucosaminuria, which can raise the suspicion of this rare disease in clinical practice.
[Mh] MeSH terms primary: Aspartylglucosaminuria/diagnostic imaging
Brain/diagnostic imaging
Brain/pathology
Magnetic Resonance Imaging
[Mh] MeSH terms secundary: Aspartylglucosaminuria/pathology
Child
Child, Preschool
Family Health
Humans
Image Processing, Computer-Assisted
Male
Turkey
[Pt] Publication type:CASE REPORTS; JOURNAL ARTICLE
[Em] Entry month:1702
[Cu] Class update date: 171001
[Lr] Last revision date:171001
[Js] Journal subset:IM
[Da] Date of entry for processing:160824
[St] Status:MEDLINE
[do] DOI:10.1177/1971400916665371


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