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Oivind Nilssen - One of the best experts on this subject based on the ideXlab platform.
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The Turkish Journal of Pediatrics 2003; 45: 46-50 Case Alpha-Mannosidosis and mutational analysis in a Turkish patient
2015Co-Authors: Akgün Ölmez, Oivind Nilssen, Helle Klenow, Turgay CoþkunAbstract:We present a case of alpha-Mannosidosis with its mutational analysis. She was referred to our hospital with the provisional diagnosis of mucolipidosis. She was the first child of second-degree relative parents. She had a coarse face with flat and wide nasal bridge, hepatosplenomegaly, umbilical hernia, lumbar gibbus, motor and mental retardation and deafness. On peripheral blood smear, lymphocytes revealed vacuoles and neutrophils contained some granules resembling Reilly bodies seen in mucopolysaccharidosis (MPS). Based on these findings, the diagnosis of alpha-Mannosidosis was suspected. Her urine oligosaccharide chromatography showed an abnormal pattern with a heavy trisaccharide band. Enzyme studies on white cells confirmed a deficiency of alpha-mannosidase activity, which was 2.6 umol/g/hr. Her DNA analysis showed a S453Y mutation. Key words: alpha-Mannosidosis, mutation, neutrophilic granules. Alpha-mannodisosis is an autosomal recessive lysosomal storage disease caused by deficiency of the enzyme acid mannosidase. Patients affected by alpha-Mannosidosis excrete increased amounts of mannose-rich oligosaccharides in the urine, and mannose-rich compounds accumulate in the various tissues of alpha-Mannosidosis patients1. The severe infantile phenotype is referred to as ‘type 1 ’ and a milder juvenile adult type is referred to as ‘type 2’. All patients have psychomotor retardation, facial coarsening and some degree of dysostosis multiplex. Common findings include recurrent bacterial infections, deafness, hepatomegaly, hernias, and lenticular or corneal opacities2. The clinical features vary in patients and several alpha-Mannosidosis causing mutations have been found, but no correlation between the types of mutations and the clinical manifestations could be shown3. In this report we present a case with alpha-Mannosidosis homozygous for a S453 mutation
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amamutdb no a relational database for man2b1 allelic variants that compiles genotypes clinical phenotypes and biochemical and structural data of mutant man2b1 in α Mannosidosis
Human Mutation, 2015Co-Authors: Hilde Monica Frostad Riise Stensland, Oivind Nilssen, Dag Malm, Helle Klenow, Gabrio Frantzen, Elina Kuokkanen, Elisabeth Kjeldsen Buvang, Pirkko HeikinheimoAbstract:α-Mannosidosis is an autosomal recessive lysosomal storage disorder caused by mutations in the MAN2B1 gene, encoding lysosomal α-mannosidase. The disorder is characterized by a range of clinical phenotypes of which the major manifestations are mental impairment, hearing impairment, skeletal changes, and immunodeficiency. Here, we report an α-Mannosidosis mutation database, amamutdb.no, which has been constructed as a publicly accessible online resource for recording and analyzing MAN2B1 variants (http://amamutdb.no). Our aim has been to offer structured and relational information on MAN2B1 mutations and genotypes along with associated clinical phenotypes. Classifying missense mutations, as pathogenic or benign, is a challenge. Therefore, they have been given special attention as we have compiled all available data that relate to their biochemical, functional, and structural properties. The α-Mannosidosis mutation database is comprehensive and relational in the sense that information can be retrieved and compiled across datasets; hence, it will facilitate diagnostics and increase our understanding of the clinical and molecular aspects of α-Mannosidosis. We believe that the amamutdb.no structure and architecture will be applicable for the development of databases for any monogenic disorder.
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The natural course and complications of alpha-Mannosidosis--a retrospective and descriptive study.
Journal of inherited metabolic disease, 2013Co-Authors: Dag Malm, Hilde Monica Frostad Riise Stensland, Øyvind Edvardsen, Oivind NilssenAbstract:Most alpha-Mannosidosis patients described have been children and information on the natural course of the disorder has been based on a very limited number of observations. In order to assess the disease presentation in detail and to study disease characteristics, a study was started in 1991 and has been ongoing for over 20 years. Patients with confirmed alpha-Mannosidosis were recruited through The International Society for Mannosidosis and Related Diseases (ISMRD) where families affected with alpha-Mannosidosis received a questionnaire on general clinical information to be filled out by the responsible physician. The questionnaire was returned by 125 patients (64 %). Of these, 45 patients were 15 years old or older at the time of evaluation. The questionnaire allowed us to assess the following features: Facial dysmorphism, columnar disease, arthritis, myopathy, hearing impairment, mental impairment, psychosis, bone disease and motor function as well as general health. This study describes the progression of alpha-Mannosidosis and may be helpful in determining the clinical characteristics for assessments of prognosis.
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Sisters with α-Mannosidosis and systemic lupus erythematosus
European Journal of Pediatrics, 2004Co-Authors: Maki Urushihara, Oivind Nilssen, Shoji Kagami, Koji Yasutomo, Shuji Kondo, Akiko Kitamura, Dag Malm, Helle Klenow, Yasuhiro KurodaAbstract:Alpha-Mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal α-mannosidase (LAMAN). Here, we report two sisters with α-Mannosidosis who developed systemic lupus erythematosus (SLE). The sisters were both homozygous for a one bp deletion within the LAMAN gene resulting in a truncated gene product. The coincidence of α-Mannosidosis and SLE are discussed with regard to both clinical and molecular findings. Conclusion: α-mannnosidosis may contribute to the onset of systemic lupus erythematosus in predisposed patients.
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Sisters with alpha-Mannosidosis and systemic lupus erythematosus.
European journal of pediatrics, 2004Co-Authors: Maki Urushihara, Oivind Nilssen, Shoji Kagami, Koji Yasutomo, Shuji Kondo, Akiko Kitamura, Dag Malm, Helle Klenow, Michinori Ito, Yasuhiro KurodaAbstract:Alpha-Mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal alpha-mannosidase (LAMAN). Here, we report two sisters with alpha-Mannosidosis who developed systemic lupus erythematosus (SLE). The sisters were both homozygous for a one bp deletion within the LAMAN gene resulting in a truncated gene product. The coincidence of alpha-Mannosidosis and SLE are discussed with regard to both clinical and molecular findings. alpha-mannnosidosis may contribute to the onset of systemic lupus erythematosus in predisposed patients.
Tommaso Beccari - One of the best experts on this subject based on the ideXlab platform.
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Alpha-Mannosidosis: Therapeutic Strategies
International journal of molecular sciences, 2018Co-Authors: Maria Rachele Ceccarini, Michela Codini, Samuela Cataldi, Elisabetta Albi, Carmela Conte, Federica Filomena Patria, Matteo Bertelli, Tommaso BeccariAbstract:Alpha-Mannosidosis (α-Mannosidosis) is a rare lysosomal storage disorder with an autosomal recessive inheritance caused by mutations in the gene encoding for the lysosomal α-d-mannosidase. So far, 155 variants from 191 patients have been identified and in part characterized at the biochemical level. Similarly to other lysosomal storage diseases, there is no relationship between genotype and phenotype in alpha-Mannosidosis. Enzyme replacement therapy is at the moment the most effective therapy for lysosomal storage disease, including alpha-Mannosidosis. In this review, the genetic of alpha-Mannosidosis has been described together with the results so far obtained by two different therapeutic strategies: bone marrow transplantation and enzyme replacement therapy. The primary indication to offer hematopoietic stem cell transplantation in patients affected by alpha-Mannosidosis is preservation of neurocognitive function and prevention of early death. The results obtained from a Phase I⁻II study and a Phase III study provide evidence of the positive clinical effect of the recombinant enzyme on patients with alpha-Mannosidosis.
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Lysosomal alpha-mannosidase and alpha-Mannosidosis.
Frontiers in Bioscience, 2017Co-Authors: Silvia Paciotti, Michela Codini, Anna Tasegian, Maria Rachele Ceccarini, Samuela Cataldi, Cataldo Arcuri, Bernard Fioretti, Elisabetta Albi, Tommaso BeccariAbstract:: Lysosomal alpha-mannosidase with acidic pH optimum is ubiquitous in human tissues where is expressed in two major forms, A and B that are the product of a single gene located on chromosome 19. Mutations in the gene encoding for alpha-mannosidase cause alpha- Mannosidosis, an autosomal recessive disease, resulting in the accumulation of unprocessed mannose containing oligosaccharide material. This rare disease has an estimated incidence of 1/500.0.00 live births and clinically is divided into three subgroups. Today the most promising therapy for this disease is the enzyme replacement therapy. To develop this strategy a mouse model for alpha-Mannosidosis has been generated and a recombinant human alpha-mannosidase has been produced from Chinese-hamster ovary cells. Interestingly it has been shown that the recombinant enzyme, used in high dose, can cross the blood brain barrier. This recombinant enzyme has been tested in the first randomized study investigating the efficacy of enzyme replacement therapy in patients with alpha-Mannosidosis. This review contains the scientific progresses on lysosomal alpha-mannosidase from the cloning to the beginning of the therapy.
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identification of two novel β Mannosidosis associated sequence variants biochemical analysis of β mannosidase manba missense mutations
Molecular Genetics and Metabolism, 2008Co-Authors: Hilde Monica Frostad Riise Stensland, Silvia Paciotti, Emanuele Persichetti, Carmelita Sorriso, Gaute Martin Hansen, Lucia Bibi, Chiara Balducci, Tommaso BeccariAbstract:Abstract β-Mannosidosis (OMIM # 248510 ) is an autosomal-recessive lysosomal storage disorder caused by deficiency of the lysosomal enzyme β-mannosidase (MANBA, E.C. 3.2.1.25). The disorder has been reported in goat, cattle and man. The human disorder is rare and only 20 cases in 16 families have been reported. We have sequenced the exons and exon–intron borders in a European patient with infantile onset of β-Mannosidosis. The patient was compound heterozygous for a silent mutation (c.375A > G) in exon 3 causing alternative splicing, and a missense mutation (c.1513T > C, p.Ser505Pro) in exon 12. The alternative splicing event deleted four nucleotides from the transcript and was predicted to result in premature termination of translation. In order to evaluate the consequence of the missense mutation, we inserted the human β-mannosidase gene into an expression vector, performed site-directed mutagenesis and expressed the normal and mutant enzyme in COS-7 cells. We also included the previously reported β-Mannosidosis-associated missense mutations c.544C > T (p.Arg182Trp) and c.1175G > A (p.Gly392Glu), which were found in patients presenting a milder phenotype. Cells transfected with the wild-type construct showed a 33-fold increase in β-mannosidase activity compared to mock-transfected cells, whereas cells transfected with the mutant constructs showed no detectable increase in activity. We propose that the milder phenotype described in some β-Mannosidosis patients with missense mutations in the MANBA gene is not due to residual β-mannosidase activity, but rather caused by epigenetic and/or environmental factors.
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targeted disruption of the lysosomal α mannosidase gene results in mice resembling a mild form of human α Mannosidosis
Human Molecular Genetics, 1999Co-Authors: Sofia Stinchi, Aldo Orlacchio, Tommaso Beccari, Renate Lullmannrauch, Dieter Hartmann, R Coenen, Kurt Von Figura, Paul SaftigAbstract:Alpha-Mannosidosis is a lysosomal storage disease with autosomal recessive inheritance caused by a deficiency of the lysosomal alpha-mannosidase, which is involved in the degradation of asparagine-linked carbohydrate cores of glycoproteins. An alpha-Mannosidosis mouse model was generated by targeted disruption of the gene for lysosomal alpha-mannosidase. Homozygous mutant animals exhibit alpha-mannosidase enzyme deficiency and elevated urinary secretion of mannose-containing oligosaccharides. Thin-layer chromatography revealed an accumulation of oligosaccharides in liver, kidney, spleen, testis and brain. The cellular alterations were characterized by multiple membrane-limited cytoplasmic vacuoles as seen for instance in liver, exocrine pancreas, kidney, thyroid gland, smooth muscle cells, osteocytes and in various neurons of the central and peripheral nervous systems. The morphological lesions and their topographical distribution, as well as the biochemical alterations, closely resemble those reported for human alpha-Mannosidosis. This mouse model will be a valuable tool for studying the pathogenesis of inherited alpha-Mannosidosis and may help to evaluate therapeutic approaches for lysosomal storage diseases.
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Lysosomal α-D-mannosidase
Bioscience Reports, 1999Co-Authors: Tommaso Beccari, Sofia Stinchi, Aldo OrlacchioAbstract:α-Mannosidosis in the human is an autosomal recessive lysosomal storage disease caused by a deficiency of lysosomal α-D-mannosidasea actvity. Lysosomal α-D-mannosidase is involved in the catabolism of N-linked glycoproteins through the sequential degradation of high-mannose, hybrid and complex oligosaccharides. This review is focused on human, mouse, bovine and feline genes coding for lysosomal α-D-mannosidase. In particular the exon-intron structure of the genes, their promoters, and the identification of mutations causing the disease have been examined. The construction, by homologous recombination, of a mouse model of α-Mannosidosis is reported.
Daniela Gasperikova - One of the best experts on this subject based on the ideXlab platform.
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Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-Mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant
Orphanet Journal of Rare Diseases, 2020Co-Authors: Dana Safka Brozkova, Lukas Varga, Anna Uhrova Meszarosova, Zuzana Slobodova, Martina Skopkova, Andrea Soltysova, Andrej Ficek, Jan Jencik, Jana Lastuvkova, Daniela GasperikovaAbstract:Background The Roma are a European ethnic minority threatened by several recessive diseases. Variants in MANBA cause a rare lysosomal storage disorder named beta-Mannosidosis whose clinical manifestation includes deafness and mental retardation. Since 1986, only 23 patients with beta-Mannosidosis and biallelic MANBA variants have been described worldwide. Results We now report on further 10 beta-Mannosidosis patients of Roma origin from eight families in the Czech and Slovak Republics with hearing loss, mental retardation and homozygous pathogenic variants in MANBA . MANBA variant c.2158-2A>G screening among 345 anonymized normal hearing controls from Roma populations revealed a carrier/heterozygote frequency of 3.77%. This is about 925 times higher than the frequency of this variant in the gnomAD public database and classifies the c.2158-2A>G variant as a prevalent, ethnic-specific variant causing hearing loss and mental retardation in a homozygous state. The frequency of heterozygotes/carriers is similar to another pathogenic variant c.71G>A (p.W24*) in GJB2 , regarded as the most frequent variant causing deafness in Roma populations. Conlcusion Beta-Mannosidosis, due to a homozygous c.2158-2A>G MANBA variant, is an important and previously unknown cause of hearing loss and mental retardation among Central European Roma.
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Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-Mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant.
Orphanet journal of rare diseases, 2020Co-Authors: Dana Safka Brozkova, Lukas Varga, Zuzana Slobodova, Martina Skopkova, Andrea Soltysova, Andrej Ficek, Jan Jencik, Jana Lastuvkova, Anna Uhrová Mészárosová, Daniela GasperikovaAbstract:The Roma are a European ethnic minority threatened by several recessive diseases. Variants in MANBA cause a rare lysosomal storage disorder named beta-Mannosidosis whose clinical manifestation includes deafness and mental retardation. Since 1986, only 23 patients with beta-Mannosidosis and biallelic MANBA variants have been described worldwide. We now report on further 10 beta-Mannosidosis patients of Roma origin from eight families in the Czech and Slovak Republics with hearing loss, mental retardation and homozygous pathogenic variants in MANBA. MANBA variant c.2158-2A>G screening among 345 anonymized normal hearing controls from Roma populations revealed a carrier/heterozygote frequency of 3.77%. This is about 925 times higher than the frequency of this variant in the gnomAD public database and classifies the c.2158-2A>G variant as a prevalent, ethnic-specific variant causing hearing loss and mental retardation in a homozygous state. The frequency of heterozygotes/carriers is similar to another pathogenic variant c.71G>A (p.W24*) in GJB2, regarded as the most frequent variant causing deafness in Roma populations. Beta-Mannosidosis, due to a homozygous c.2158-2A>G MANBA variant, is an important and previously unknown cause of hearing loss and mental retardation among Central European Roma.
John J. Hopwood - One of the best experts on this subject based on the ideXlab platform.
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Behavioural characterisation of the α-Mannosidosis guinea pig
Behavioural brain research, 2007Co-Authors: A.j. Robinson, Allison C. Crawley, Dyane Auclair, P.f. Weston, C. Hirte, Kim M. Hemsley, John J. HopwoodAbstract:Abstract α-Mannosidosis is a lysosomal storage disorder resulting from a functional deficiency of the lysosomal enzyme α-mannosidase. This deficiency results in the accumulation of various oligosaccharides in the lysosomes of affected individuals, causing somatic pathology and progressive neurological degeneration that results in cognitive deficits, ataxia, and other neurological symptoms. We have a naturally occurring guinea pig model of this disease which exhibits a deficiency of lysosomal α-mannosidase and has a similar clinical presentation to human α-Mannosidosis. Various tests were developed in the present study to characterise and quantitate the loss of neurological function in α-Mannosidosis guinea pigs and to follow closely the progression of the disease. General neurological examinations showed progressive differences in α-Mannosidosis animals from approximately 1 month of age. Significant differences were observed in hind limb gait width from 2 months of age and significant cognitive (memory and learning) deficits were observed from 3 months of age. Evoked response tests showed an increase in somatosensory P1 peak latency in α-Mannosidosis guinea pigs from approximately 2 months of age, as well as progressive hearing loss using auditory brainstem evoked responses. The α-Mannosidosis guinea pig therefore appears to exhibit many of the characteristics of the human disease, and will be useful in evaluating therapies for treatment of central nervous system pathology.
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Enzyme replacement therapy in alpha-Mannosidosis guinea-pigs.
Molecular genetics and metabolism, 2006Co-Authors: Allison C. Crawley, Thomas Berg, Barbara King, Peter J Meikle, John J. HopwoodAbstract:alpha-Mannosidosis is a lysosomal storage disorder caused by deficient activity of lysosomal alpha-mannosidase and is characterised by massive accumulation of mannose-containing oligosaccharides in affected individuals. Patients develop behaviour and learning difficulties, skeletal abnormalities, immune deficiency and hearing impairment. Disease in alpha-Mannosidosis guinea-pigs resembles the clinical, histopathological, biochemical and molecular features of the human disease. We have used the guinea-pig model to investigate efficacy of enzyme replacement therapy as a treatment for alpha-Mannosidosis. Intravenous recombinant human lysosomal alpha-mannosidase, administered at a dose of 1mg/kg, was cleared from circulation with a half-life of 53 h, with significant enzyme activity (1.4x normal levels) detected in circulation one week post-injection. alpha-Mannosidase administered to alpha-Mannosidosis guinea-pigs at 1mg/kg (onset at birth or approximately 30 days) and 10mg/kg (at birth) was distributed widely amongst tissues, including to capillary depleted brain. By monitoring with tandem mass spectrometry, enzyme replacement therapy was found to be effective in reducing stored substrates in peripheral tissues at both dose rates, and in brain by up to 39% at the 10mg/kg dose, compared with untreated alpha-Mannosidosis controls. Reductions of up to 60% of urinary mannose containing oligosaccharides were also observed. No histological improvements were seen in the brain at either dose, however marked decreases in lysosomal vacuolation in liver, kidney, spleen and endocrine pancreas, as well as a significant reduction in trigeminal ganglion neurons were observed. Multiple injections of 1mg/kg recombinant enzyme in alpha-Mannosidosis guinea-pigs induced a very rapid humoral immune response precluding long-term intravenous treatment.
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Enzyme replacement therapy in α-Mannosidosis guinea-pigs
Molecular Genetics and Metabolism, 2006Co-Authors: Allison C. Crawley, Thomas Berg, Barbara King, Peter J Meikle, John J. HopwoodAbstract:alpha-Mannosidosis is a lysosomal storage disorder caused by deficient activity of lysosomal alpha-mannosidase and is characterised by massive accumulation of mannose-containing oligosaccharides in affected individuals. Patients develop behaviour and learning difficulties, skeletal abnormalities, immune deficiency and hearing impairment. Disease in alpha-Mannosidosis guinea-pigs resembles the clinical, histopathological, biochemical and molecular features of the human disease. We have used the guinea-pig model to investigate efficacy of enzyme replacement therapy as a treatment for alpha-Mannosidosis. Intravenous recombinant human lysosomal alpha-mannosidase, administered at a dose of 1mg/kg, was cleared from circulation with a half-life of 53 h, with significant enzyme activity (1.4x normal levels) detected in circulation one week post-injection. alpha-Mannosidase administered to alpha-Mannosidosis guinea-pigs at 1mg/kg (onset at birth or approximately 30 days) and 10mg/kg (at birth) was distributed widely amongst tissues, including to capillary depleted brain. By monitoring with tandem mass spectrometry, enzyme replacement therapy was found to be effective in reducing stored substrates in peripheral tissues at both dose rates, and in brain by up to 39% at the 10mg/kg dose, compared with untreated alpha-Mannosidosis controls. Reductions of up to 60% of urinary mannose containing oligosaccharides were also observed. No histological improvements were seen in the brain at either dose, however marked decreases in lysosomal vacuolation in liver, kidney, spleen and endocrine pancreas, as well as a significant reduction in trigeminal ganglion neurons were observed. Multiple injections of 1mg/kg recombinant enzyme in alpha-Mannosidosis guinea-pigs induced a very rapid humoral immune response precluding long-term intravenous treatment.
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α-Mannosidosis in the guinea pig: cloning of the lysosomal α-mannosidase cDNA and identification of a missense mutation causing α-Mannosidosis
Biochimica et biophysica acta, 2002Co-Authors: Thomas Berg, John J. HopwoodAbstract:Abstract α-Mannosidosis is a lysosomal storage disorder caused by deficient activity of the lysosomal α-mannosidase. We report here the sequencing and expression of the lysosomal α-mannosidase cDNA from normal and α-Mannosidosis guinea pigs. The amino acid sequence of the guinea pig enzyme displayed 82–85% identity to the lysosomal α-mannosidase in other mammals. The cDNA of the α-Mannosidosis guinea pig contained a missense mutation, 679C>T, leading to substitution of arginine by tryptophan at amino acid position 227 (R227W). The R227W allele segregated with the α-Mannosidosis genotype in the guinea pig colony and introduction of R227W into the wild-type sequence eliminated the production of recombinant α-mannosidase activity in heterologous expression studies. Furthermore, the guinea pig mutation has been found in human patients. Our results strongly indicate that the 679C>T mutation causes α-Mannosidosis and suggest that the guinea pig will be an excellent model for investigation of pathogenesis and evaluation of therapeutic strategies for human α-Mannosidosis.
Margaret Z. Jones - One of the best experts on this subject based on the ideXlab platform.
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Inheritance of β‐Mannosidosis in goats
Animal Genetics, 2009Co-Authors: R. A. Fisher, Cavanagh K, E. J. S. Rathke, J A Kelley, Margaret Z. JonesAbstract:Plasma levels of beta-mannosidase activity were measured in the phenotypically normal members of a family of goats in which 12 cases of beta-Mannosidosis have been reported. Normal or carrier genotypes were assigned on the basis of these results, and mating tables drawn up. Similar data were collected on a number of other small families unrelated to the one with beta-Mannosidosis. The results indicate that the plasma beta-mannosidase level is a reasonably good indicator of carrier status and confirm that the disease beta-Mannosidosis is inherited in a recessive manner and is not X-linked.
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Identification of a bovine β-Mannosidosis mutation and detection of two β-mannosidase pseudogenes
Mammalian Genome, 1999Co-Authors: J.r. Leipprandt, Margaret Z. Jones, Hong Chen, Juliann E. Horvath, Xiao Tan Qiao, Karen H FridericiAbstract:β-Mannosidase deficiency results in β-Mannosidosis, a severe neurodegenerative lysosomal storage disease identified in cattle, goats, and humans. To more fully understand the molecular pathology of this disease, the mutation associated with bovine β-Mannosidosis was identified by sequence analysis of cDNA from an affected calf. A transition mutation of G to A at position 2574 of the cDNA coding sequence creates a premature stop codon near the 3′ end of the protein coding region. To aid commercial breeders of Salers cattle, a PCR-based test was developed to detect the mutation for β-Mannosidosis carrier screening. Application of this test also revealed the presence of two β-mannosidase pseudogenes. Portions of the pseudogenes were amplified with allele-specific primers and then sequenced. One pseudogene was highly homologous (>99% sequence identity) to the expressed cDNA sequence over the 1292 bp that were sequenced, while the other showed more divergence (83% sequence identity) in the 477 bp that were sequenced. Both are processed pseudogenes that are not expressed. The severity of the bovine β-Mannosidosis phenotype suggests that the 22 C-terminal amino acids of β-mannosidase play an important role in the function of this enzyme.
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BIOCHEMICAL AND MORPHOLOGICAL EXPRESSION OF EARLY PRENATAL CAPRINE β‐Mannosidosis
Prenatal diagnosis, 1997Co-Authors: Kathryn L Lovell, Jon S Patterson, F. Matsuura, G. Baeverfjord, N. K. Ames, Margaret Z. JonesAbstract:Lysosomal storage diseases associated with early-onset pathological changes may require prenatal therapy to avert the profound effects of the metabolic error on organs, especially the central nervous system. The present investigation determined the extent of expression of beta-mannosidase deficiency in the caprine fetus at 62 days of gestation, near the end of the period of immunotolerance when donor cells can engraft in various organs without immune rejection and supply missing enzyme. Three pairs of obligate carrier goats from the beta-Mannosidosis colony were mated. Out of six fetuses delivered at 62 days of gestation, one (V385) was identified by measurement of beta-mannosidase activity as the only fetus affected with beta-Mannosidosis. Thin-layer chromatography and quantitation of oligosaccharides revealed the presence of tri- and disaccharides, typical of beta-Mannosidosis, only in V385. Morphological analysis revealed cytoplasmic vacuolation typical of beta-Mannosidosis in V385; in thyroid, spinal cord, and kidney, the pattern of vacuolation was similar to, but less severe than, that observed previously in newborn affected goats. On the basis of these results, it will be possible to determine the effects of prenatal cell transplantation therapeutic strategies performed during the period of immunotolerance by monitoring phenotypic characteristics after treatment.
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Caprine β-Mannosidase: Sequencing and Characterization of the cDNA and Identification of the Molecular Defect of Caprine β-Mannosidosis
Genomics, 1996Co-Authors: J.r. Leipprandt, Kevin T. Cavanagh, Karen H Friderici, Stacey A. Kraemer, Benjamin E. Haithcock, Hong Chen, Joshua L. Dyme, Margaret Z. JonesAbstract:The complete sequence of the caprine beta-mannosidase cDNA coding region has been determined, and a mutation that is associated with caprine beta-Mannosidosis has been identified. Reverse transcriptase-polymerase chain reactions were performed using primers based on bovine and, later, goat cDNA sequences to produce an overlapping series of amplicons covering the entire coding region. The composite cDNA codes for an 879-amino-acid peptide that has four potential N-glycosylation sites. Comparison of the caprine and bovine cDNAs reveals that 96.3% of the nucleotides and 95.2% of the deduced amino acids are identical. A single-base deletion at position 1398 of the coding sequence was identified in the cDNA isolated from a goat affected with beta-Mannosidosis. This deletion results in a shift in the reading frame and a premature termination of translation, yielding a deduced peptide of 481 amino acids. An assay, developed to determine the presence or absence of this mutation, confirmed that animals affected with beta-Mannosidosis were homozygous for the mutation and that obligate carriers in a caprine beta-Mannosidosis colony were heterozygous. This assay accurately distinguished between mutation carrier and noncarrier goats and was used for prenatal diagnosis using DNA collected from fetal fluids. The assay also confirmed chimerism in a goat with an atypically mild beta-Mannosidosis phenotype. Thus, this application enables assessment of the efficacy of engraftment of hematopoietic stem cells after prenatal transfer from donor sources.
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Oligosaccharides accumulated in the bovineβ-Mannosidosis kidney
Journal of inherited metabolic disease, 1992Co-Authors: Margaret Z. Jones, E. J. S. Rathke, Douglas A. Gage, Catherine E. Costello, K. Murakami, M. Ohta, F. MatsuuraAbstract:The phenotype of bovine beta-Mannosidosis (beta-mannosidase deficiency), recently identified in Salers cattle, is similar to the caprine form of the disease (Abbitt et al., 1991). This investigation was designed to characterize accumulated kidney oligosaccharides in bovine beta-Mannosidosis. Oligosaccharides were extracted from the kidney of an affected Salers calf and purified by chromatographic techniques. The amount of accumulating oligosaccharides in 1 g of wet tissue was about 21 mumol. Structures of derivatized oligosaccharides were characterized by high-performance liquid chromatography, mass spectrometry, methylation analysis and sequential exoglycosidase digestions. The major accumulating oligosaccharides were Man beta 1-4GlcNAc and Man beta 1-4GlcNAc beta 1-4GlcNAc. Oligosaccharides accumulating in minor amounts were Man beta 1-4GlcNAc beta 1-4Man beta 1-4GlcNAc, Man alpha 1-6Man beta 1-4GlcNAc beta 1-4GlcNAc and Man beta 1-4GlcNAc beta 1-4Man beta 1-4GlcNAc beta 1-4GlcNAc. As in caprine beta-Mannosidosis, oligosaccharides with terminal beta-mannose residues and cleaved as well as uncleaved chitobiose linkages were identified in bovine beta-Mannosidosis kidney. The accumulating oligosaccharides in tissue were thus identical in bovine and caprine beta-Mannosidosis; however, the source of the novel oligosaccharides remains to be determined.