Database : MEDLINE
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PMID:28007910
Author:Hooper AWM; Alamilla JF; Venier RE; Gillespie DC; Igdoura SA
Address:Department of Biology.
Title:Neuronal pentraxin 1 depletion delays neurodegeneration and extends life in Sandhoff disease mice.
Source:Hum Mol Genet; 26(4):661-673, 2017 Feb 15.
ISSN:1460-2083
Country of publication:England
Language:eng
Abstract:GM2 gangliosidoses are a group of lysosomal storage disorders which include Sandhoff disease and Tay-Sachs disease. Dysregulation of glutamate receptors has been recently postulated in the pathology of Sandhoff disease. Glutamate receptor association with neuronal pentraxins 1 and 2, and the neuronal pentraxin receptor facilitates receptor potentiation and synaptic shaping. In this study, we have observed an upregulation of a novel form of neuronal pentraxin 1 (NP1-38) in the brains of a mouse model of Sandhoff disease and Tay-Sachs disease. In order to determine the impact of NP1 on the pathophysiology of Sandhoff disease mouse models, we have generated an Np1-/-Hexb-/- double knockout mouse, and observed extended lifespan, improved righting reflex and enhanced body condition relative to Hexb-/- mice, with no effect on gliosis or apoptotic markers in the CNS. Sandhoff mouse brain slices reveals a reduction in AMPA receptor-mediated currents, and increased variability in total glutamate currents in the CA1 region of the hippocampus; Np1-/-Hexb-/- mice show a correction of this phenotype, suggesting NP1-38 may be interfering with glutamate receptor function. Indeed, some of the psychiatric aspects of Sandhoff and Tay-Sachs disease (particularly late onset) may be attributed to a dysfunctional hippocampal glutamatergic system. Our work highlights a potential role for synaptic proteins, such as NP1 and glutamate receptors in lysosomal storage diseases.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Nerve Tissue Proteins); 0 (neuronal pentraxin); 9007-41-4 (C-Reactive Protein); EC 3.2.1.52 (beta-Hexosaminidase beta Chain)


  2 / 46 MEDLINE  
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PMID:27725117
Author:Hooper AW; Igdoura SA
Address:Department of Biology, McMaster University, Hamilton, Ont. L8S 4K1, Canada. Electronic address: hooperaw@Mcmaster.ca.
Title:Bi-phasic gliosis drives neuropathology in a Sandhoff disease mouse model.
Source:J Neuroimmunol; 299:19-27, 2016 10 15.
ISSN:1872-8421
Country of publication:Netherlands
Language:eng
Abstract:Microgliosis and astrogliosis are known to be exacerbating factors in the progression of the lysosomal storage disorder Sandhoff disease. We have also found evidence for excitotoxicity via glutamate receptors in Sandhoff disease. To view the interaction of these cascades, we measured cerebellar expression of markers for gliosis, apoptosis, and excitatory synapses over the disease course in a Sandhoff disease mouse model. We observe a 2-stage model, with initial activation of microgliosis as early as 60days of age, followed by a later onset of astrogliosis, caspase-mediated apoptosis, and reduction in GluR1 at approximately 100days of age. These results implicate immune cells as first responders in Sandhoff disease.
Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Name of substance:EC 3.2.1.52 (HEXB protein, human); EC 3.2.1.52 (beta-Hexosaminidase beta Chain)


  3 / 46 MEDLINE  
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PMID:27682710
Author:Abiri M; Talebi S; Uitto J; Youssefian L; Vahidnezhad H; Shirzad T; Salehpour S; Zeinali S
Title:Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity.
Source:J Pediatr Endocrinol Metab; 29(10):1215-1219, 2016 Oct 01.
ISSN:2191-0251
Country of publication:Germany
Language:eng
Abstract:Most inborn errors of metabolism (IEMs) are inherited in an autosomal recessive manner. IEMs are one of the major concerns in Iran due to its extensive consanguineous marriages. Herein, we report two patients with two co-existent IEMs: a girl affected by classic phenylketonuria (PKU) and maple syrup urine disease (MSUD) and a male patient affected with Sandhoff disease and PKU, where Sandhoff disease was suspected due to the presence of a cherry-red spot in the eyes at 6 months which is unrelated to PKU. Sequencing of candidate genes in the first patient revealed one novel and three recurrent compound heterozygous mutations of p.Ser231Pro and p.Ala300Ser in the PAH gene and p.Glu330Lys and p.Arg170Cys mutations in the BCKDHB gene. Genetic testing results in the second patient showed previously reported homozygous mutations of p.Arg261Gln in the PAH and p.Arg533Cys mutation in the HEXB gene. Genetic testing confirmed the clinical diagnosis of both diseases in both patients. To the best of our knowledge; this is the first report of the co-existence of two distinct genetic disorders in two individuals from Iran. Co-existent different IEMs in patients complicated the clinical diagnosis and management of the diseases.
Publication type:CASE REPORTS; JOURNAL ARTICLE
Name of substance:0 (Biomarkers); EC 3.2.1.52 (HEXB protein, human); EC 3.2.1.52 (beta-Hexosaminidase beta Chain)


  4 / 46 MEDLINE  
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PMID:27233122
Author:Krejzová J; Kulik N; Slámová K; Kren V
Address:Laboratory of Biotransformation, Institute of Microbiology, Czech Academy of Sciences, Vídenská 1083, CZ 14220 Praha 4, Czech Republic; Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 5, CZ 16628 Praha 6, Czech Republic. Electronic address: janak
Title:Expression of human ß-N-acetylhexosaminidase B in yeast eases the search for selective inhibitors.
Source:Enzyme Microb Technol; 89:1-6, 2016 Jul.
ISSN:1879-0909
Country of publication:United States
Language:eng
Abstract:Human lysosomal ß-N-acetylhexosaminidases from the family 20 of glycoside hydrolases are dimeric enzymes catalysing the cleavage of terminal ß-N-acetylglucosamine and ß-N-acetylgalactosamine residues from a broad spectrum of glycoconjugates. Here, we present a facile, robust, and cost-effective extracellular expression of human ß-N-acetylhexosaminidase B in Pichia pastoris KM71H strain. The prepared Hex B was purified in a single step with 33% yield obtaining 10mg of the pure enzyme per 1L of the culture media. The enzyme was used in the inhibition assays with the known mechanism-based inhibitor NAG-thiazoline and a wide variety of its derivatives in the search for specific inhibitors of the human GH20 ß-N-acetylhexosaminidases over the human GH84 ß-N-acetylglucosaminidase, which was expressed, purified and used in the inhibition experiments as well. Moreover, enzyme-inhibitor complexes were analysed employing computational tools in order to reveal the structural basis of the results of the inhibition assays, showing the importance of water-mediated interactions between the enzyme and respective ligands. The presented method for the heterologous expression of human Hex B is robust, it significantly reduces the costs and equipment demands in comparison to the expression in mammalian cell lines. This will enhance accessibility of this human enzyme to the broad scientific community and may speed up the research of specific inhibitors of this physiologically important glycosidase family.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Enzyme Inhibitors); 0 (Recombinant Proteins); 0 (Thiazoles); EC 3.2.1.52 (HEXB protein, human); EC 3.2.1.52 (beta-Hexosaminidase beta Chain); ML5FHL557A (N-acetylglucosamine thiazoline); V956696549 (Acetylglucosamine)


  5 / 46 MEDLINE  
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PMID:27018595
Author:Kitakaze K; Mizutani Y; Sugiyama E; Tasaki C; Tsuji D; Maita N; Hirokawa T; Asanuma D; Kamiya M; Sato K; Setou M; Urano Y; Togawa T; Otaka A; Sakuraba H; Itoh K
Title:Protease-resistant modified human ß-hexosaminidase B ameliorates symptoms in GM2 gangliosidosis model.
Source:J Clin Invest; 126(5):1691-703, 2016 May 02.
ISSN:1558-8238
Country of publication:United States
Language:eng
Abstract:GM2 gangliosidoses, including Tay-Sachs and Sandhoff diseases, are neurodegenerative lysosomal storage diseases that are caused by deficiency of ß-hexosaminidase A, which comprises an αß heterodimer. There are no effective treatments for these diseases; however, various strategies aimed at restoring ß-hexosaminidase A have been explored. Here, we produced a modified human hexosaminidase subunit ß (HexB), which we have termed mod2B, composed of homodimeric ß subunits that contain amino acid sequences from the α subunit that confer GM2 ganglioside-degrading activity and protease resistance. We also developed fluorescent probes that allow visualization of endocytosis of mod2B via mannose 6-phosphate receptors and delivery of mod2B to lysosomes in GM2 gangliosidosis models. In addition, we applied imaging mass spectrometry to monitor efficacy of this approach in Sandhoff disease model mice. Following i.c.v. administration, mod2B was widely distributed and reduced accumulation of GM2, asialo-GM2, and bis(monoacylglycero)phosphate in brain regions including the hypothalamus, hippocampus, and cerebellum. Moreover, mod2B administration markedly improved motor dysfunction and a prolonged lifespan in Sandhoff disease mice. Together, the results of our study indicate that mod2B has potential for intracerebrospinal fluid enzyme replacement therapy and should be further explored as a gene therapy for GM2 gangliosidoses.
Publication type:JOURNAL ARTICLE
Name of substance:EC 3.2.1.52 (HEXB protein, human); EC 3.2.1.52 (beta-Hexosaminidase beta Chain); EC 3.4.- (Peptide Hydrolases)


  6 / 46 MEDLINE  
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PMID:26582265
Author:Tamhankar PM; Mistri M; Kondurkar P; Sanghavi D; Sheth J
Address:Genetic Research Center, National Institute for Research in Reproductive Health, Mumbai, India.
Title:Clinical, biochemical and mutation profile in Indian patients with Sandhoff disease.
Source:J Hum Genet; 61(2):163-6, 2016 Feb.
ISSN:1435-232X
Country of publication:England
Language:eng
Abstract:Sandhoff disease (SD) is an autosomal recessive neurodegenerative lysosomal storage disorder caused by mutations in HEXB gene. Molecular pathology is unknown in Indian patients with SD. The present study is aimed to determine mutations spectrum and molecular pathology leading to SD in 22 unrelated patients confirmed by the deficiency of ß-hexosaminidase-A and total-hexosaminidase in leukocytes. To date, nearly 86 mutations of HEXB have been described, including five large deletions. Over all we have identified 13 mutations in 19 patients, eight of which were novel, including two missense mutations [c.611G>A (p.G204E), c. 634A>T (p.H212Y)], two nonsense mutations [c.333G>A (p.W111X), c.298C>T (p.R100X)], one splice site mutation c.1082+5 G>T, two small in-frame deletions [c.534_541delAGTTTATC (p.V179RfsX10), c.1563_1573delTATGGATGACG (p.M522LfsX2)] and one insertion c.1553_1554insAAGA (p.D518EfsX8). We have also identified previously known, five sequence variations leading to amino acid changes [c.926G>A (p.C309Y), c.1597C>T (p.R533C)], one nonsense mutation c.850 C>T (p.R284X), one splice site mutation c.1417+1 G-A and one insertion c.1591_1592insC (p.R531TfsX22). Mutation was not identified in three patients. We observed from this study that mutation c.850C>T (p.R284X) was identified in 4/19 (21%) patients which is likely to be the most common mutation in the country. This is the first study providing insight into the molecular basis of SD in India.
Publication type:JOURNAL ARTICLE
Name of substance:EC 3.2.1.52 (HEXB protein, human); EC 3.2.1.52 (beta-Hexosaminidase beta Chain)


  7 / 46 MEDLINE  
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PMID:26020229
Author:Couceiro R; Fonseca A; Campos F
Title:Toddler with retinal defects. . .psychomotor regression. Sandhoff disease.
Source:J Pediatr Ophthalmol Strabismus; 52(3):138-9, 176, 2015 May-Jun.
ISSN:1938-2405
Country of publication:United States
Language:eng
Publication type:CASE REPORTS; JOURNAL ARTICLE
Name of substance:EC 3.2.1.52 (beta-Hexosaminidase alpha Chain); EC 3.2.1.52 (beta-Hexosaminidase beta Chain)


  8 / 46 MEDLINE  
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PMID:25736553
Author:Grunseich C; Schindler AB; Chen KL; Bakar D; Mankodi A; Traslavina R; Ray-Chaudhury A; Lehky TJ; Baker EH; Maragakis NJ; Tifft CJ; Fischbeck KH
Address:Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, 20892, USA, Christopher.grunseich@nih.gov.
Title:Peripheral neuropathy in a family with Sandhoff disease and SH3TC2 deficiency.
Source:J Neurol; 262(4):1066-8, 2015.
ISSN:1432-1459
Country of publication:Germany
Language:eng
Publication type:CASE REPORTS; LETTER; RESEARCH SUPPORT, N.I.H., INTRAMURAL
Name of substance:0 (Proteins); 0 (SH3TC2 protein, human); EC 3.2.1.52 (HEXB protein, human); EC 3.2.1.52 (beta-Hexosaminidase beta Chain)


  9 / 46 MEDLINE  
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PMID:25515709
Author:Walia JS; Altaleb N; Bello A; Kruck C; LaFave MC; Varshney GK; Burgess SM; Chowdhury B; Hurlbut D; Hemming R; Kobinger GP; Triggs-Raine B
Address:1] Department of Pediatrics, Queen's University, Kingston, Ontario, Canada [2] Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada [3] Department of Pediatrics & Child Health, University of Manitoba, Winnipeg, Manitoba, Canada [4] Manitoba Instit
Title:Long-term correction of Sandhoff disease following intravenous delivery of rAAV9 to mouse neonates.
Source:Mol Ther; 23(3):414-22, 2015 Mar.
ISSN:1525-0024
Country of publication:United States
Language:eng
Abstract:G(M2) gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in ß-hexosaminidase A activity and lacking effective therapies. Using a Sandhoff disease (SD) mouse model (Hexb(-/-)) of the G(M2) gangliosidoses, we tested the potential of systemically delivered adeno-associated virus 9 (AAV9) expressing Hexb cDNA to correct the neurological phenotype. Neonatal or adult SD and normal mice were intravenously injected with AAV9-HexB or -LacZ and monitored for serum ß-hexosaminidase activity, motor function, and survival. Brain G(M2) ganglioside, ß-hexosaminidase activity, and inflammation were assessed at experimental week 43, or an earlier humane end point. SD mice injected with AAV9-LacZ died by 17 weeks of age, whereas all neonatal AAV9-HexB-treated SD mice survived until 43 weeks (P < 0.0001) with only three exhibiting neurological dysfunction. SD mice treated as adults with AAV9-HexB died between 17 and 35 weeks. Neonatal SD-HexB-treated mice had a significant increase in brain ß-hexosaminidase activity, and a reduction in G(M2) ganglioside storage and neuroinflammation compared to adult SD-HexB- and SD-LacZ-treated groups. However, at 43 weeks, 8 of 10 neonatal-HexB injected control and SD mice exhibited liver or lung tumors. This study demonstrates the potential for long-term correction of SD and other G(M2) gangliosidoses through early rAAV9 based systemic gene therapy.
Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., INTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
Name of substance:19600-01-2 (G(M2) Ganglioside); EC 3.2.1.52 (beta-Hexosaminidase beta Chain)


  10 / 46 MEDLINE  
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PMID:24915922
Author:Huang Y; Xie T; Zheng J; Zhao X; Liu H; Liu L
Address:Department of Endocrinology and Metabolism, Guangzhou Women and Children's Medical Center, Guangzhou 510623, China.
Title:[Clinical and molecular characteristics of a child with juvenile Sandhoff disease].
Source:Zhonghua Er Ke Za Zhi; 52(4):313-6, 2014 Apr.
ISSN:0578-1310
Country of publication:China
Language:chi
Abstract:OBJECTIVE: To explore the clinical features and molecular mutation of HEXB gene in a case with juvenile Sandhoff disease. METHOD: We retrospectively reviewed the clinical, neuroimaging and biochemical findings in this Chinese child with juvenile Sandhoff disease. Hexosaminidase A and hexosaminidase A & B activities were measured in blood leukocytes by fluorometric assay. HEXB gene molecular analysis was performed by PCR and direct sequencing. RESULT: The 9-year-old boy was admitted for psychomotor regression. He presented slowly progressive gait disorder and dysarthria during the last three years. Cranial MRI revealed a marked cerebellar atrophy with normal intensity in the thalamus and basal ganglia. Brain MRS showed normal in the thalamus and basal ganglia. Hexosaminidase A was 69.5 (mg·h) [normal controls 150-360 nmol/(mg·h)], hexosaminidase A & B activity was 119 nmol/(mg·h)[normal controls 600-3 500 nmol/(mg·h)], confirming the diagnosis of Sandhoff disease. The patient was a compound heterozygote for a novel deletion mutation c.1404delT (p. P468P fsX62) and a reported mutation c.1509-26G>A. CONCLUSION: The clinical features of juvenile Sandhoff disease include ataxia, dysarthria and cerebellar atrophy. The enzyme assay and molecular analysis of HEXB gene can confirm the diagnosis of Sandhoff disease. The novel mutation c.1404delT(p. P468P fsX62) is a disease-related mutation.
Publication type:CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Name of substance:EC 3.2.1.52 (HEXB protein, human); EC 3.2.1.52 (Hexosaminidase A); EC 3.2.1.52 (Hexosaminidase B); EC 3.2.1.52 (beta-Hexosaminidase beta Chain)



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