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Proceedings of the National Academy of... Jun 2022Macroautophagy promotes cellular homeostasis by delivering cytoplasmic constituents to lysosomes for degradation [Mizushima, 20, 521-527 (2018)]. However, while most...
Macroautophagy promotes cellular homeostasis by delivering cytoplasmic constituents to lysosomes for degradation [Mizushima, 20, 521-527 (2018)]. However, while most studies have focused on the mechanisms of protein degradation during this process, we report here that macroautophagy also depends on glycan degradation via the glycosidase, α-l-fucosidase 1 (FUCA1), which removes fucose from glycans. We show that cells lacking FUCA1 accumulate lysosomal glycans, which is associated with impaired autophagic flux. Moreover, in a mouse model of fucosidosis-a disease characterized by inactivating mutations in [Stepien , 11, E1383 (2020)]-glycan and autophagosome/autolysosome accumulation accompanies tissue destruction. Mechanistically, using lectin capture and mass spectrometry, we identified several lysosomal enzymes with altered fucosylation in FUCA1-null cells. Moreover, we show that the activity of some of these enzymes in the absence of FUCA1 can no longer be induced upon autophagy stimulation, causing retardation of autophagic flux, which involves impaired autophagosome-lysosome fusion. These findings therefore show that dysregulated glycan degradation leads to defective autophagy, which is likely a contributing factor in the etiology of fucosidosis.
Topics: Animals; Fucosidosis; Lysosomes; Macroautophagy; Mice; Polysaccharides; alpha-L-Fucosidase
PubMed: 35737835
DOI: 10.1073/pnas.2111506119 -
Genes Nov 2020Fucosidosis is a neurodegenerative disorder which progresses inexorably. Clinical features include coarse facial features, growth retardation, recurrent upper... (Review)
Review
Fucosidosis is a neurodegenerative disorder which progresses inexorably. Clinical features include coarse facial features, growth retardation, recurrent upper respiratory infections, dysostosis multiplex, and angiokeratoma corporis diffusum. Fucosidosis is caused by mutations in the gene resulting in α-L-fucosidase deficiency. Only 36 pathogenic variants in the gene are related to fucosidosis. Most of them are missense/nonsense substitutions; six missense and 11 nonsense mutations. Among deletions there were eight small and five gross changes. So far, only three splice site variants have been described-one small deletion, one complete deletion and one stop-loss mutation. The disease has a significant clinical variability, the cause of which is not well understood. The genotype-phenotype correlation has not been well defined. This review describes the genetic profile and clinical manifestations of fucosidosis in pediatric and adult cases.
Topics: Animals; Disease Models, Animal; Enzyme Replacement Therapy; Fucosidosis; Genetic Association Studies; Hematopoietic Stem Cell Transplantation; Humans; Molecular Diagnostic Techniques; Prenatal Diagnosis; alpha-L-Fucosidase
PubMed: 33266441
DOI: 10.3390/genes11111383 -
Frontiers in Veterinary Science 2020Mouse models of human disease remain the bread and butter of modern biology and therapeutic discovery. Nonetheless, more often than not mouse models do not reproduce the... (Review)
Review
Mouse models of human disease remain the bread and butter of modern biology and therapeutic discovery. Nonetheless, more often than not mouse models do not reproduce the pathophysiology of the human conditions they are designed to mimic. Naturally occurring large animal models have predominantly been found in companion animals or livestock because of their emotional or economic value to modern society and, unlike mice, often recapitulate the human disease state. In particular, numerous models have been discovered in dogs and have a fundamental role in bridging proof of concept studies in mice to human clinical trials. The present article is a review that highlights current canine models of human diseases, including Alzheimer's disease, degenerative myelopathy, neuronal ceroid lipofuscinosis, globoid cell leukodystrophy, Duchenne muscular dystrophy, mucopolysaccharidosis, and fucosidosis. The goal of the review is to discuss canine and human neurodegenerative pathophysiologic similarities, introduce the animal models, and shed light on the ability of canine models to facilitate current and future treatment trials.
PubMed: 32219101
DOI: 10.3389/fvets.2020.00080 -
Neurology India 2022
Topics: Humans; Fucosidosis
PubMed: 36352683
DOI: 10.4103/0028-3886.359164 -
BMC Pediatrics Jul 2022Fucosidosis is one of the rare autosomal recessive lysosomal storage diseases (LSDs) attributed to FUCA1 variants causing the deficiency of α-L-fucosidase in vivo.... (Review)
Review
BACKGROUND
Fucosidosis is one of the rare autosomal recessive lysosomal storage diseases (LSDs) attributed to FUCA1 variants causing the deficiency of α-L-fucosidase in vivo. Α-L-fucosidase deficiency will cause excessive accumulation of fucosylated glycoproteins and glycolipids, which eventually leads to dysfunction in all tissue systems and presents with multiple symptoms. Fucosidosis is a rare disease which is approximately 120 cases have been reported worldwide (Wang, L. et al., J Int Med Res 48, 1-6, 2020). The number of reported cases in China is no more than 10 (Zhang, X. et al., J Int Med Res 49:3000605211005975, 2021).
CASE PRESENTATION
The patient was an 8-year-old Chinese boy who presented with postnatal motor retardation, intellectual disability, short stature, language development retardation, coarse facial features, hepatomegaly, and diffuse angiokeratoma of both palms. His genetic testing showed the presence of a homozygous pathogenic variant (c.671delC) in the FUCA1 gene. In addition, the enzymatic activity of α-L-fucosidase was low. Ultimately, the patient was diagnosed with fucosidosis.
CONCLUSIONS
Fucosidosis is a rare lysosomal storage disease because of FUCA1 variants that cause the deficiency of α-L-fucosidase in vivo. An explicit diagnosis requires a combination of clinical manifestations, imaging examination, genetic testing and enzyme activity analysis. Early diagnosis plays an important role in fucosidosis.
Topics: Asian People; Child; Fucosidosis; Homozygote; Humans; Male; Mutation; alpha-L-Fucosidase
PubMed: 35820891
DOI: 10.1186/s12887-022-03414-y -
The Turkish Journal of Pediatrics 2022Fucosidosis is a rare, autosomal recessive lysosomal storage disease caused by alpha L- fucosidase enzyme deficiency in all tissues. Here, we identify a patient with a...
BACKGROUND
Fucosidosis is a rare, autosomal recessive lysosomal storage disease caused by alpha L- fucosidase enzyme deficiency in all tissues. Here, we identify a patient with a novel homozygous pathogenic variant and atypical clinical findings and summarized the clinical and molecular features of Turkish patients reported in the literature and present.
CASE
The patient was born to consangineous parents at the 28th week of gestation. He had developmental delay that was attributed to prematurity. At he age of 2.5 years, brain magnetic resonans imaging revealed hyperintensities of symmetrical periventricular, subcortical, centrum semiovale and corona radiata regions on T2 and FLAIR weighted images. He developed seizures and showed developmental regression at he age of 3,5 years. Beside, coarse facial features and hepatomegaly were detected on phsyical examination. Lysosomal enzyme analysis revelaed alfa fucosidase deficiency and molecular genetic analysis identified a novel homozygous pathogenic p. Lys431 fs variant in FUCA1 gene.
CONCLUSIONS
In Turkish patients no distinguishable clinical and radiologic finding could be established. Molecular analysis was performed in few patients. Increasing of molecular and biochemical facilities might enable to make diagnosis and increase the prevalence of the disease in countries with high rate of consanguineous marriages. Moreover, it will provide genetic counseling, and enlighten the therapeutic effects of hematopoietic stem cell transplantation.
Topics: Brain; Child, Preschool; Fucosidosis; Homozygote; Humans; Male; alpha-L-Fucosidase
PubMed: 36082656
DOI: 10.24953/turkjped.2021.4852 -
Journal of Pediatric Neurosciences May 2014Fucosidosis is a rare lysosomal storage disorder due to deficiency of fucosidase enzyme, with around 100 cases reported worldwide. Here, we describe the clinical and...
Fucosidosis is a rare lysosomal storage disorder due to deficiency of fucosidase enzyme, with around 100 cases reported worldwide. Here, we describe the clinical and imaging features in two siblings with fucosidosis. An 8-year-old girl presented with global developmental delay, followed by regression of acquired milestones from 3 years of age with bipyramidal, extrapyramidal involvement, coarse facies, telangiectatic lesions, dysostosis multiplex, characteristic magnetic resonance imaging finding along with undetectable levels of the fucosidase activity, which confirmed the diagnosis. Younger sibling has mild developmental delay with autistic traits with no neuroregression until now. He also has undetectable level of fucosidase enzyme activity and is being considered for stem cell transplantation. New case reports would expand the clinical spectrum, early diagnosis and help formulating appropriate therapy. Early diagnosis is crucial and hence sibling screening can be done, and those in the presymptomatic stage can undergo hematopoietic stem cell transplantation, which is potentially curable.
PubMed: 25250075
DOI: 10.4103/1817-1745.139331 -
Cells Jun 2020The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis,... (Review)
Review
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
Topics: Animals; Enzyme Replacement Therapy; Glycoproteins; Hematopoietic Stem Cell Transplantation; Humans; Lysosomal Storage Diseases
PubMed: 32517081
DOI: 10.3390/cells9061411 -
The Tohoku Journal of Experimental... Jan 1973
Topics: Carbohydrate Metabolism, Inborn Errors; Child, Preschool; Female; Fibroblasts; Glycolipids; Glycopeptides; Glycosaminoglycans; Glycoside Hydrolases; Humans; Hydrogen-Ion Concentration; Leukocytes; Liver; Microscopy, Electron; Skin; Uronic Acids
PubMed: 4268654
DOI: 10.1620/tjem.109.41 -
Biochimica Et Biophysica Acta Oct 1999Glycoproteinoses belong to the lysosomal storage disorders group. The common feature of these diseases is the deficiency of a lysosomal protein that is part of glycan... (Review)
Review
Glycoproteinoses belong to the lysosomal storage disorders group. The common feature of these diseases is the deficiency of a lysosomal protein that is part of glycan catabolism. Most of the lysosomal enzymes involved in the hydrolysis of glycoprotein carbohydrate chains are exo-glycosidases, which stepwise remove terminal monosaccharides. Thus, the deficiency of a single enzyme causes the blockage of the entire pathway and induces a storage of incompletely degraded substances inside the lysosome. Different mutations may be observed in a single disease and in all cases account for the nonexpression of lysosomal glycosidase activity. Different clinical phenotypes generally characterize a specific disorder, which rather must be described as a continuum in severity, suggesting that other biochemical or environmental factors influence the course of the disease. This review provides details on clinical features, genotype-phenotype correlations, enzymology and biochemical storage of four human glycoprotein lysosomal storage disorders, respectively alpha- and beta-mannosidosis, fucosidosis and alpha-N-acetylgalactosaminidase deficiency. Moreover, several animal disorders of glycoprotein metabolism have been found and constitute valuable models for the understanding of their human counterparts.
Topics: Animals; Carbohydrate Sequence; Congenital Disorders of Glycosylation; Disease Models, Animal; Fucosidosis; Glycoside Hydrolases; Hexosaminidases; Humans; Molecular Sequence Data; Phenotype; alpha-Mannosidosis; alpha-N-Acetylgalactosaminidase
PubMed: 10571005
DOI: 10.1016/s0925-4439(99)00077-0