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Ilkka Mononen – 1st expert on this subject based on the ideXlab platform
Aspartylglycosaminuria: a reviewOrphanet Journal of Rare Diseases, 2016Co-Authors: Maria Arvio, Ilkka MononenAbstract:
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.
Aspartylglycosaminuria a reviewOrphanet Journal of Rare Diseases, 2016Co-Authors: Maria Arvio, Ilkka MononenAbstract:
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.
Early initiation of enzyme replacement therapy improves metabolic correction in the brain tissue of Aspartylglycosaminuria miceJournal of Inherited Metabolic Disease, 2010Co-Authors: Ulla Dunder, Pirjo Valtonen, Eira Kelo, Ilkka MononenAbstract:
Aspartylglycosaminuria (AGU) is a lysosomal storage disease caused by deficient activity of glycosylasparaginase (AGA), and characterized by motor and mental retardation. Enzyme replacement therapy (ERT) in adult AGU mice with AGA removes the accumulating substance aspartylglucosamine from and reverses pathology in many somatic tissues, but has only limited efficacy in the brain tissue of the animals. In the current work, ERT of AGU mice was initiated at the age of 1 week with three different dosage schedules of recombinant glycosylasparaginase. The animals received either 3.4 U of AGA/kg every second day for 2 weeks (Group 1), 1.7 U/kg every second day for 9 days followed by an enzyme injection once a week for 4 weeks (Group 2) or 17 U/kg at the age of 7 and 9 days (Group 3). In the Group 1 and Group 3 mice, ERT reduced the amount of aspartylglucosamine by 34 and 41% in the brain tissue, respectively. No therapeutic effect was observed in the brain tissue of Group 2 mice. As in the case of adult AGU mice, the AGA therapy was much more effective in the somatic tissues than in the brain tissue of the newborn AGU mice. The combined evidence demonstrates that a high dose ERT with AGA in newborn AGU mice is up to twofold more effective in reducing the amount of the accumulated storage material from the brain tissue than ERT in adult AGU animals, indicating the importance of early detection and treatment of the disease.
Vesa Kaartinen – 2nd expert on this subject based on the ideXlab platform
enzyme replacement therapy in a mouse model of AspartylglycosaminuriaThe FASEB Journal, 2000Co-Authors: Ulla Dunder, John Groffen, Nora Heisterkamp, Vesa Kaartinen, Pirjo Valtonen, Eira Vaananen, Velimatti Kosma, Ilkka MononenAbstract:
Aspartylglycosaminuria (AGU), the most common lysosomal disorder of glycoprotein degradation, is caused by deficient activity of glycosylasparaginase (AGA). AGA-deficient mice share most of the clinical, biochemical and histopathologic characteristics of human AGU disease. In the current study, recombinant human AGA administered i.v. to adult AGU mice disappeared from the systemic circulation of the animals in two phases predominantly into non-neuronal tissues, which were rapidly cleared from storage compound aspartylglucosamine. Even a single AGA injection reduced the amount of aspartylglucosamine in the liver and spleen of AGU mice by 90% and 80%, respectively. Quantitative biochemical analyses along with histological and immunohistochemical studies demonstrated that the pathophysiologic characteristics of AGU were effectively corrected in non-neuronal tissues of AGU mice during 2 wk of AGA therapy. At the same time, AGA activity increased to 10% of that in normal brain tissue and the accumulation of as…
progressive neurodegeneration in Aspartylglycosaminuria miceAmerican Journal of Pathology, 1998Co-Authors: Ignacio Gonzalezgomez, Ilkka Mononen, John Groffen, Nora Heisterkamp, Vesa KaartinenAbstract:
Aspartylglycosaminuria (AGU) is one of the most common lysosomal storage disorders in humans. A mouse model for AGU has been recently generated through targeted disruption of the glycosylasparaginase gene, and at a young age the glycosyl asparaginase-deficient mice demonstrated many pathological changes found in human AGU patients (Kaartinen V, Mononen I, Voncken J-W, Gonzalez-Gomez I, Heisterkamp N, Groffen J: A mouse model for Aspartylglycosaminuria. Nat Med 1996, 2:1375–1378). Our current findings demonstrate that after the age of 10 months, the general condition of null mutant mice gradually deteriorated. They suffered from a progressive motoric impairment and impaired bladder function and died prematurely. A widespread lysosomal hypertrophy in the central nervous system was detected. This neuronal vacuolation was particularly severe in the lateral thalamic nuclei, medullary reticular nuclei, vestibular nuclei, inferior olivary complex, and deep cerebellar nuclei. The oldest animals (20 months old) displayed a clear neuronal loss and gliosis, particularly in those regions, where the most severe vacuolation was found. The severe ataxic gait of the older mice was likely due to the dramatic loss of Purkinje cells, intensive astrogliosis and vacuolation of neurons in the deep cerebellar nuclei, and the severe vacuolation of the cells in vestibular and cochlear nuclei. The impaired bladder function and subsequent hydronephrosis were secondary to involvement of the central nervous system. These findings demonstrate that the glycosylasparaginase-deficient mice share many neuropathological features with human AGU patients, providing a suitable animal model to test therapeutic strategies in the treatment of the central nervous system effects in AGU.
A mouse model for the human lysosomal disease AspartylglycosaminuriaNature Medicine, 1996Co-Authors: Vesa Kaartinen, Ilkka Mononen, Nora Heisterkamp, Jan Willem Voncken, Tiina Noronkoski, Ignacio Gonzalez-gomez, John GroffenAbstract:
Aspartylglycosaminuria (AGU), the most common disorder of glycoprotein degradation in humans, is caused by mutations in the gene encoding the lysosomal enzyme glycosylasparaginase (Aga)^1. The resulting enzyme deficiency allows aspartylglucosamine (GlcNAc–Asn) and other glycoasparagines to accumulate in tissues and body fluids, from early fetal life onward^1. The clinical course is characterized by normal early development, slowly progressing to severe mental and motor retardation in early adulthood^2,3. The exact pathogenesis of AGU in humans is unknown and neither therapy nor an animal model for this debilitating and ultimately fatal disease exists. Through targeted disruption of the mouse Aga gene in embryonic stem cells, we generated mice that completely lack Aga activity. At the age of 5–10 months a massive accumulation of GlcNAc–Asn was detected along with lysosomal vacuolization, axonal swelling in the gracile nucleus and impaired neuromotor coordination. A significant number of older male mice had massively swollen bladders, which was not caused by obstruction, but most likely related to the impaired function of the nervous system. These findings are consistent with the pathogenesis of AGU and provide further data explaining the impaired neurological function in AGU patients.
Nathan N Aronson – 3rd expert on this subject based on the ideXlab platform
Aspartylglycosaminuria biochemistry and molecular biologyBiochimica et Biophysica Acta, 1999Co-Authors: Nathan N AronsonAbstract:
Abstract Aspartylglucosaminuria (AGU, McKusick 208400) is an autosomal recessive lysosomal storage disease caused by defective degradation of Asn-linked glycoproteins. AGU mutations occur in the gene (AGA) for glycosylasparaginase, the enzyme necessary for hydrolysis of the protein–oligosaccharide linkage in Asn-linked glycoprotein substrates undergoing metabolic turnover. Loss of glycosylasparaginase activity leads to accumulation of the linkage unit Asn–GlcNAc in tissue lysosomes. Storage of this fragment affects the pathophysiology of neuronal cells most severely. The patients notably suffer from decreased cognitive abilities, skeletal abnormalities and facial grotesqueness. The progress of the disease is slower than in many other lysosomal storage diseases. The patients appear normal during infancy and generally live from 25 to 45 years. A specific AGU mutation is concentrated in the Finnish population with over 200 patients. The carrier frequency in Finland has been estimated to be in the range of 2.5–3% of the population. So far there are 20 other rare family AGU alleles that have been characterized at the molecular level in the world’s population. Recently, two knockout mouse models for AGU have been developed. In addition, the crystal structure of human leukocyte glycosylasparaginase has been determined and the protein has a unique αββα sandwich fold shared by a newly recognized family of important enzymes called N-terminal nucleophile (Ntn) hydrolases. The nascent single-chain precursor of glycosylase araginase self-cleaves into its mature α- and β-subunits, a reaction required to activate the enzyme. This interesting biochemical feature is also shared by most of the Ntn-hydrolase family of proteins. Many of the disease-causing mutations prevent proper folding and subsequent activation of the glycosylasparaginase.
lysosomal storage disease Aspartylglycosaminuria, 1997Co-Authors: Nathan N Aronson, Ilkka ManonenAbstract:
This is a review of Aspartylglycosaminuria (AGU), which is one of the most common lysosomal diseases worldwide. It gives an overview of the disease from its discovery and early history to recent developments. It also provides detailed reference material for clinical specialists and researchers working in the field of inborn errors of metabolism, in particular on lysosomal diseases.
Glycosylation and Phosphorylation of Lysosomal GlycosylasparaginaseArchives of Biochemistry and Biophysics, 1996Co-Authors: Hyejeong Park, Michelle Vettese-dadey, Nathan N AronsonAbstract:
Abstract Glycosylasparaginase (EC 188.8.131.52) is a lysosomal amidase which hydrolyzes the bond between asparagine and the sugar moiety in N-linked glycoproteins. Deficiency of the enzyme results in Aspartylglycosaminuria (AGU), the most common disorder of glycoprotein degradation. Mature enzyme is formed by two proteolytic cleavage steps subsequent to removal of its signal peptide: (1) an activation cleavage in the ER of the initial single-chain 49-kDa polypeptide into a 27-kDa α- and 19-kDa β-subunit; (2) a cleavage in lysosomes which removes 10 amino acids from the C-terminus of the α-subunit without affecting enzyme activity. Each subunit of glycosylasparaginase contains one N-linked oligosaccharide (N38, α-subunit; N308, β-subunit). Both oligosaccharides were phosphorylated and releasable by Endo-H digestion, indicating they were of the high-mannose type. These glycosylation sequenons were mutagenized to determine the role of the oligosaccharide at each site in proper folding and transport of glycosylasparaginase. An N38D mutant underwent the lysosomal processing step, indicating that targeting to lysosomes can be via the phosphorylated β-subunit oligosaccharide alone. Deletion of the β-subunit oligosaccharide at N308 by an aspartic acid substitution resulted in very little protein or enzyme activity in the transfected cells, reemphasizing that glycosylation of the β-subunit site is important for efficient folding and/or targeting. A different mutation to eliminate the same N-glycosylation sequenon (T310A) yielded more protein and enzyme activity, and a double mutant N38D/T310A yielded the same results as the single β-subunit substitution. Yield of enzyme for all mutants was increased in cells treated with brefeldin A. The N308 glycosylation site of the β-subunit appears to be more important in maintaining normal transport and stability of human glycosylasparaginase.