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Pediatric Neurology Mar 2023
Topics: Humans; beta-Mannosidosis
PubMed: 36706484
DOI: 10.1016/j.pediatrneurol.2022.12.012 -
Biochimie Jan 1992Lysosomal beta-D-mannosidase is the last exoglycosidase involved in the sequential degradation of the N-glycosylproteins glycans. Research on this enzyme was restricted... (Review)
Review
Lysosomal beta-D-mannosidase is the last exoglycosidase involved in the sequential degradation of the N-glycosylproteins glycans. Research on this enzyme was restricted before the discovery of its hereditary deficiency, first in goat (1981) and later in man (1986). We describe the biochemical aspects of these beta-mannosidosis and the properties of the beta-mannosidases of mammalian origin. Our own results concerning human enzyme (from kidney and urine, seminal plasma and blood cells) suggest that, apart from the case of the inherited disease, beta-mannosidase may become a useful tool in other pathologies.
Topics: Animals; Goat Diseases; Goats; Humans; Mannosidases; alpha-Mannosidosis; beta-Mannosidase
PubMed: 1576208
DOI: 10.1016/0300-9084(92)90179-i -
Ryoikibetsu Shokogun Shirizu 1998
Review
Topics: Diagnosis, Differential; Humans; Mannose; Mannosidases; Prognosis; alpha-Mannosidosis; beta-Mannosidase
PubMed: 9645109
DOI: No ID Found -
Veterinary Pathology Sep 2019A neurological disease was investigated in 3 German Shepherd pups from the same litter that failed to grow normally, appeared stiff, were reluctant to move, and were...
A neurological disease was investigated in 3 German Shepherd pups from the same litter that failed to grow normally, appeared stiff, were reluctant to move, and were deaf. They developed intermittent seizures and ataxia and had proprioceptive defects. Histopathology showed severe vacuolation of neurons, astrocytes in nervous tissue, renal tubular epithelial cells, and macrophages in nervous tissue, spleen, and liver. Vacuoles appeared empty with no storage material stained by periodic acid-Schiff (PAS) or Sudan black stains, leading to a diagnosis of a lysosomal storage disease and in particular an oligosaccharidosis. Biochemical and genomic studies showed that this was β-mannosidosis, not previously diagnosed in dogs. A c.560T>A transition in exon 4 of the gene was found, which segregated in these and other family members in a manner consistent with it being the causative mutation of an autosomal recessive disease. This mutation led to substitution of isoleucine to asparagine at position 187 of the 885 amino acid enzyme, a change expected to have functional significance.
Topics: Animals; Cerebrum; Dog Diseases; Dogs; Gene Expression Regulation, Enzymologic; Genetic Predisposition to Disease; Genotyping Techniques; Male; Mannosidases; Mutation, Missense; Whole Genome Sequencing; beta-Mannosidosis
PubMed: 30983534
DOI: 10.1177/0300985819839239 -
Pediatric Pulmonology Apr 2023
Topics: Humans; beta-Mannosidosis; alpha-Mannosidosis; Hemorrhage
PubMed: 36610029
DOI: 10.1002/ppul.26310 -
Molecular Genetics and Metabolism 2019Hereditary β-mannosidosis causing progressive lysosomal neuropathy and other clinical signs, has been previously described in humans, Nubian goats, and Salers cattle....
Hereditary β-mannosidosis causing progressive lysosomal neuropathy and other clinical signs, has been previously described in humans, Nubian goats, and Salers cattle. Here we report the clinicopathological, metabolic, and molecular genetic features of canine beta-mannosidase (MANBA, EC 3.2.1.25) deficiency. A 1-year-old male mix-breed dog from St. Kitts was presented with progressive stumbling, weakness, and regurgitation. Vacuolated lymphocytes were observed on the blood film. Postmortem findings included marked enlargement of nerves, megaesophagus, and internal hydrocephalus. Vacuolated macrophages, neurons, and secretory epithelial cells suggested an oligosaccharide storage disease. Plasma concentration of the β-mannosidosis specific oligosaccharide was approximately 75 fold that of controls. The plasma beta-mannosidase activity was severely reduced to ~5% of controls; five other lysosomal acid hydrolase activities were increased or within their normal reference interval. Genomic sequencing of this dog's MANBA gene identified a homozygous exonic five bp tandem duplication in the penultimate exon of the MANBA gene (c.2377_2381dupTATCA) which results in a reading frame shift, altering the subsequent amino acid sequence and creating a premature stop codon. The truncated beta-mannosidase enzyme is expected to be dysfunctional. This enzyme deficiency causes the accumulation of un-degraded oligosaccharides in cells, which affect the myelination of the peripheral and central nervous systems. This insertion was not encountered in 121 and 80-screened samples from dogs on St. Kitts (all were homozygous for wild-type) and Philadelphia region (wild-type), respectively. In conclusion, canine β-mannosidosis has similar clinicopathological features with some human patients, but milder signs than in ruminants and more severe than in knockout mice. Hence, dogs with β-mannosidosis could become a valuable disease model for the human disease.
Topics: Animals; Codon, Nonsense; DNA Mutational Analysis; Dog Diseases; Dogs; Exons; Male; Mutation; beta-Mannosidase; beta-Mannosidosis
PubMed: 31439511
DOI: 10.1016/j.ymgme.2019.08.002 -
Gene Jan 2024A 6-month-old cat of unknown ancestry presented for a neurologic evaluation due to progressive motor impairment. Complete physical and neurologic examinations suggested...
A 6-month-old cat of unknown ancestry presented for a neurologic evaluation due to progressive motor impairment. Complete physical and neurologic examinations suggested the disorder was likely to be hereditary, although the signs were not consistent with any previously described inherited disorders in cats. Due to the progression of disease signs including severely impaired motor function and cognitive decline, the cat was euthanized at approximately 10.5 months of age. Whole genome sequence analysis identified a homozygous missense variant c.2506G > A in MANBA that predicts a p.Gly836Arg alteration in the encoded lysosomal enzyme β -mannosidase. This variant was not present in the whole genome or whole exome sequences of any of the 424 cats represented in the 99 Lives Cat Genome dataset. β -Mannosidase enzyme activity was undetectable in brain tissue homogenates from the affected cat, whereas α-mannosidase enzyme activities were elevated compared to an unaffected cat. Postmortem examination of brain and retinal tissues revealed massive accumulations of vacuolar inclusions in most cells, similar to those reported in animals of other species with hereditary β -mannosidosis. Based on these findings, the cat likely suffered from β -mannosidosis due to the abolition of β -mannosidase activity associated with the p.Gly836Arg amino acid substitution. p.Gly836 is located in the C-terminal region of the protein and was not previously known to be involved in modulating enzyme activity. In addition to the vacuolar inclusions, some cells in the brain of the affected cat contained inclusions that exhibited lipofuscin-like autofluorescence. Electron microscopic examinations suggested these inclusions formed via an autophagy-like process.
Topics: Cats; Animals; beta-Mannosidosis; beta-Mannosidase; Mutation, Missense
PubMed: 37913889
DOI: 10.1016/j.gene.2023.147941 -
Journal of Pediatric Neurosciences 2021β-Mannosidosis is a rare lysosomal storage disorder that is caused by a deficiency of β-mannosidase activity, which is due to mutations of the gene. Two Indian...
β-Mannosidosis is a rare lysosomal storage disorder that is caused by a deficiency of β-mannosidase activity, which is due to mutations of the gene. Two Indian siblings born out of a third-degree consanguineous marriage presented during late infancy with global developmental delay. On examination, both the siblings had hypotonia; hepatosplenomegaly was present in the first sibling whereas it was absent in the second sibling. Fundus evaluation, hearing assessment, and skeletal survey were normal in both siblings. Enzyme assay showed the absence of the β-mannosidase enzyme. Next-generation sequencing showed a homozygous variation of c.1317 + 1G>A in intron 10 of the MANBA (-) gene in the elder sibling. Sanger sequencing confirmed the same mutation in the homozygous state in both siblings and in the heterozygous state in both parents.
PubMed: 35018184
DOI: 10.4103/jpn.JPN_65_20 -
The FEBS Journal Apr 2019β-Mannosidase is a lysosomal enzyme from the glycosyl hydrolase family 2 that cleaves the single β(1-4)-linked mannose at the nonreducing end of N-glycosylated...
β-Mannosidase is a lysosomal enzyme from the glycosyl hydrolase family 2 that cleaves the single β(1-4)-linked mannose at the nonreducing end of N-glycosylated proteins, and plays an important role in the polysaccharide degradation pathway. Mutations in the MANBA gene, which encodes the β-mannosidase, can lead to the lysosomal storage disease β-mannosidosis, as well as nystagmus, an eye condition characterized by involuntary eye movements. Here, we present the first structures of a mammalian β-mannosidase in both the apo- and mannose-bound forms. The structure is similar to previously determined β-mannosidase structures with regard to domain organization and fold, however, there are important differences that underlie substrate specificity between species. Additionally, in contrast to most other ligand-bound β-mannosidases from bacterial and fungal sources where bound sugars were in a boat-like conformation, we find the mannose in the chair conformation. Evaluation of known disease mutations in the MANBA gene provides insight into their impact on disease phenotypes. Together, these results will be important for the design of therapeutics for treating diseases caused by β-mannosidase deficiency. DATABASE: Structural data are available in the Protein Data Bank under the accession numbers 6DDT and 6DDU.
Topics: Amino Acid Sequence; Animals; Catalytic Domain; Glycosylation; Humans; Mannose; Mice; Mutation; Nystagmus, Pathologic; Phenotype; Protein Conformation; Sequence Homology; Substrate Specificity; beta-Mannosidase; beta-Mannosidosis
PubMed: 30552791
DOI: 10.1111/febs.14731 -
Cold Spring Harbor Molecular Case... Jun 2019β-Mannosidosis is a lysosomal storage disorder characterized by accumulation of disaccharides due to deficiency of the lysosomal enzyme β-mannosidase. The disease is...
β-Mannosidosis is a lysosomal storage disorder characterized by accumulation of disaccharides due to deficiency of the lysosomal enzyme β-mannosidase. The disease is caused by mutations in and is extremely rare in humans. Although the clinical presentation is heterogeneous, common symptoms include various degrees of developmental delay, behavioral disturbances, hearing loss, and frequent infections. We report a 15-yr-old girl presenting with mild intellectual disability, sensorineural hearing loss, severe behavioral disturbances, dysmorphic traits, and evolving angiokeratomas. Copy-number variation analysis of next-generation sequencing (NGS) data indicated increased coverage in exons 8-11 of Low β-mannosidase activity (1 µkatal/kg protein, refv 25-40) established the diagnosis of β-mannosidosis. Whole-genome sequencing (WGS) and cDNA analysis revealed a novel homozygous intragenic inverted duplication in where a 13.1-kb region between introns 7 and 11 was duplicated and inserted in an inverted orientation, creating a 67-base nonduplicated gap at the insertion point. Both junctions showed microhomology regions. The inverted duplication resulted in exon skipping of exons 8-9 or 8-10. Our report highlights the importance of copy-number variation analysis of data from NGS and in particular the power of WGS in the identification and characterization of copy-number variants.
Topics: Adolescent; Angiokeratoma; DNA Copy Number Variations; DNA, Complementary; Exons; Female; Gene Duplication; Hearing Loss; High-Throughput Nucleotide Sequencing; Homozygote; Humans; Intellectual Disability; Mannosidases; Mutation; Phenotype; Sequence Analysis, DNA; Whole Genome Sequencing; beta-Mannosidosis
PubMed: 30886116
DOI: 10.1101/mcs.a003954