The Experts below are selected from a list of 369 Experts worldwide ranked by ideXlab platform

Carole Vogler - One of the best experts on this subject based on the ideXlab platform.

  • to human and mouse β-glucuronidase
    2006
    Co-Authors: Shunji Tomatsu, Carole Vogler, Jeffrey H. Grubb, Kazuko Sukegawa, Koji O. Orii, Elizabeth M. Snella, Monica A. Gutierrez, Tatiana Dieter, Christopher C. Holden, Naomi Kondo
    Abstract:

    Mucopolysaccharidosis VII (MPS VII, Sly Syndrome) is an autosomal recessive lysosomal storage disease caused by β-glucuronidase (GUS) deficiency. A naturally occurring mouse model of that disease has been very useful for studying experimental approaches to therapy. However, immune responses can complicate evaluation of the long-term benefits of enzyme replacement or gene therapy delivered to adult MPS VII mice. To make this model useful for studying the long-term effectiveness and side effects of experimental therapies delivered to adult mice, we developed a new MPS VII mouse model, which is tolerant to both human and murine GUS. To achieve this, we used homologous recombination to introduce simultaneouSly a human cDNA transgene expressing inactive human GUS into intron 9 of the murine Gus gene and a targeted active site mutation (E536A) into the adjacent exon 10. When the heterozygote products of germline transmission were bred to homozygosity, the homozygous mice expressed no GUS enzyme activity but expressed inactive human GUS protein highly and were tolerant to immune challenge with human enzyme. Expression of the mutant murine Gus gene was reduced to about 10% of normal levels, but the inactive murine GUS enzyme also conferred tolerance to murine GUS. This MPS VII mouse model should be useful to evaluate therapeutic responses in adult mice receiving repetitive doses of enzyme or mice receiving gene therapy as adults. Heterozygotes expressed only 9.5–26% of wild-type levels of murine GUS instead of the expected 50%, indicating a dominant-negative effect of the mutant enzyme monomers on the activity of GUS tetramers in different tissues. Corrective gene therapy in this model should provide high enough levels of expression of normal GUS monomers to overcome the dominant negative effect of mutant monomers on newly synthesized GUS tetramers in most tissues.

  • Electrocardiographic and other cardiac anomalies in β-glucuronidase-null mice corrected by nonablative neonatal marrow transplantation
    Proceedings of the National Academy of Sciences, 2004
    Co-Authors: Adam J.t Schuldt, Carole Vogler, Nancy Galvin, Mark D. Lessard, T. J. Hampton, V. Chu, Jane E. Barker
    Abstract:

    Cardiovascular manifestations of lysosomal storage disease (LSD) are a significant health problem for affected patients. Infantileonset cardiac disease, because of its rapid progression, is usually treated symptomatically. Therapy in older patients includes valve replacement and bone marrow (BM) transplantation, both of which are life threatening in the already debilitated patients. Enzyme replacement therapy has potential benefit but has not yet been demonstrated to provide long-term relief for cardiac disease. Here, we demonstrate prevention of severe cardiac manifestations in β-glucuronidase (GUSB) null mice BM-transplanted i.v. as neonates without myeloablative pretreatment. The mice, a model of mucopolysaccharidosis type VII (MPSVII, Sly Syndrome), develop progressive LSD unless provided with GUSB early in life. The BM recipients retained GUSB+ donor cells in the peripheral blood and heart until necropsy at >11 months of age. The enzyme β-hexosamindase increased in tissues of GUSB null MPSVII mice was reduced significantly (P = 0.001) in treated MPSVII hearts. Electrocardiography demonstrated normalization of heart rate, PR, PQ, and QRS intervals in BM recipients. Storage was markedly reduced in the stroma of heart valves, adventitial cells of the aortic root, perivascular and interstitial cells of the myocardium, and interstitial cells of the conduction tissue. Heart/body weight ratio normalized. The aortic root was still grosSly distended, and the conductive myocytes retained storage, suggesting neither plays a major role in ECG normalization. We conclude that transplantation of MPSVII neonates without toxic intervention can prevent many of the cardiovascular manifestations of LSD.

  • Production of MPS VII mouse (Gustm(hE540A.mE536A)Sly) doubly tolerant to human and mouse β-glucuronidase
    Human molecular genetics, 2003
    Co-Authors: Shunji Tomatsu, Carole Vogler, Jeffrey H. Grubb, Kazuko Sukegawa, Koji O. Orii, Elizabeth M. Snella, Monica A. Gutierrez, Tatiana Dieter, Christopher C. Holden, Tadao Orii
    Abstract:

    Mucopolysaccharidosis VII (MPS VII, Sly Syndrome) is an autosomal recessive lysosomal storage disease caused by β-glucuronidase (GUS) deficiency. A naturally occurring mouse model of that disease has been very useful for studying experimental approaches to therapy. However, immune responses can complicate evaluation of the long-term benefits of enzyme replacement or gene therapy delivered to adult MPS VII mice. To make this model useful for studying the long-term effectiveness and side effects of experimental therapies delivered to adult mice, we developed a new MPS VII mouse model, which is tolerant to both human and murine GUS. To achieve this, we used homologous recombination to introduce simultaneouSly a human cDNA transgene expressing inactive human GUS into intron 9 of the murine Gus gene and a targeted active site mutation (E536A) into the adjacent exon 10. When the heterozygote products of germline transmission were bred to homozygosity, the homozygous mice expressed no GUS enzyme activity but expressed inactive human GUS protein highly and were tolerant to immune challenge with human enzyme. Expression of the mutant murine Gus gene was reduced to about 10% of normal levels, but the inactive murine GUS enzyme also conferred tolerance to murine GUS. This MPS VII mouse model should be useful to evaluate therapeutic responses in adult mice receiving repetitive doses of enzyme or mice receiving gene therapy as adults. Heterozygotes expressed only 9.5–26% of wild-type levels of murine GUS instead of the expected 50%, indicating a dominant-negative effect of the mutant enzyme monomers on the activity of GUS tetramers in different tissues. Corrective gene therapy in this model should provide high enough levels of expression of normal GUS monomers to overcome the dominant negative effect of mutant monomers on newly synthesized GUS tetramers in most tissues.

  • Missense models [Gustm(E536A)Sly, Gustm(E536Q)Sly, and Gustm(L175F)Sly] of murine mucopolysaccharidosis type VII produced by targeted mutagenesis.
    Proceedings of the National Academy of Sciences of the United States of America, 2002
    Co-Authors: Shunji Tomatsu, Carole Vogler, Jeffrey H. Grubb, Kazuko Sukegawa, Tadao Orii, Koji O. Orii, Elizabeth M. Snella, Monica A. Gutierrez, Tatiana Dieter, Naomi Kondo
    Abstract:

    Human mucopolysaccharidosis VII (MPS VII, Sly Syndrome) results from a deficiency of β-glucuronidase (GUS) and has been associated with a wide range in severity of clinical manifestations. To study missense mutant models of murine MPS VII with phenotypes of varying severity, we used targeted mutagenesis to produce E536A and E536Q, corresponding to active-site nucleophile replacements E540A and E540Q in human GUS, and L175F, corresponding to the most common human mutation, L176F. The E536A mouse had no GUS activity in any tissue and displayed a severe phenotype like that of the originally described MPS VII mice carrying a deletion mutation (gusmps/mps). E536Q and L175F mice had low levels of residual activity and milder phenotypes. All three mutant MPS models showed progressive lysosomal storage in many tissues but had different rates of accumulation. The amount of urinary glycosaminoglycan excretion paralleled the clinical severity, with urinary glycosaminoglycans remarkably higher in E536A mice than in E536Q or L175F mice. Molecular analysis showed that the Gus mRNA levels were quantitatively similar in the three mutant mouse strains and normal mice. These mouse models, which mimic different clinical phenotypes of human MPS VII, should be useful in studying pathogenesis and also provide useful models for studying enzyme replacement therapy and targeted correction of missense mutations.

  • Production of MPS VII mouse (Gustm(hE540AmE536A)Sly) doubly tolerant to human and mouse b-glucuronidase
    2002
    Co-Authors: Shunji Tomatsu, Carole Vogler, Jeffrey H. Grubb, Koji O. Orii, Elizabeth M. Snella, Monica Gutierrez, Tatiana Dieterchristopher, C. Holden, Kazuko Sukegawatadao, Oriinaomi Kondowilliam
    Abstract:

    Mucopolysaccharidosis VII (MPS VII, Sly Syndrome) is an autosomal recessive lysosomal storage disease caused by b-glucuronidase (GUS) deficiency. A naturally occurring mouse model of that disease has been very useful for studying experimental approaches to therapy. However, immune responses can complicate evaluation of the long-term benefits of enzyme replacement or gene therapy delivered to adult MPS VII mice. To make this model useful for studying the long-term effectiveness and side effects of experimental therapies delivered to adult mice, we developed a new MPS VII mouse model, which is tolerant to both human and murine GUS. To achieve this, we used homologous recombination to introduce simultaneouSly a human cDNA transgene expressing inactive human GUS into intron 9 of the murine Gus gene and a targeted active site mutation (E536A) into the adjacent exon 10. When the heterozygote products of germline transmission were bred to homozygosity, the homozygous mice expressed no GUS enzyme activity but expressed inactive human GUS protein highly and were tolerant to immune challenge with human enzyme. Expression of the mutant murine Gus gene was reduced to about 10 % of normal levels, but the inactive murine GUS enzyme also conferred tolerance to murine GUS. This MPS VII mouse model should be useful to evaluate therapeutic responses in adult mice receiving repetitive doses of enzyme or mice receiving gene therapy as adults. Heterozygotes expressed only 9.5–26 % of wild-type levels of murine GUS instead of the expected 50%

William S. Sly - One of the best experts on this subject based on the ideXlab platform.

  • First human treatment with investigational rhGUS enzyme replacement therapy in an advanced stage MPS VII patient.
    Molecular genetics and metabolism, 2014
    Co-Authors: Joyce E. Fox, Emil D Kakkis, Linda Volpe, Josephine Bullaro, William S. Sly
    Abstract:

    Mucopolysaccharidosis type VII (MPS VII, Sly Syndrome) is a very rare lysosomal storage disease caused by a deficiency of the enzyme β-glucuronidase (GUS), which is required for the degradation of three glycosaminoglycans (GAGs): dermatan sulfate, heparan sulfate, and chondroitin sulfate. Progressive accumulation of these GAGs in lysosomes leads to increasing dysfunction in numerous tissues and organs. Enzyme replacement therapy (ERT) has been used successfully for other MPS disorders, but there is no approved treatment for MPS VII. Here we describe the first human treatment with recombinant human GUS (rhGUS), an investigational therapy for MPS VII, in a 12-year old boy with advanced stage MPS VII. Despite a tracheostomy, nocturnal continuous positive airway pressure, and oxygen therapy, significant pulmonary restriction and obstruction led to oxygen dependence and end-tidal carbon dioxide (ETCO2) levels in the 60-80mmHg range, eventually approaching respiratory failure (ETCO2 of 100mmHg) and the need for full-time ventilation. Since no additional medical measures could improve his function, we implemented experimental ERT by infusing rhGUS at 2mg/kg over 4h every 2 weeks for 24 weeks. Safety was evaluated by standard assessments and observance for any infusion associated reactions (IARs). Urinary GAG (uGAG) levels, pulmonary function, oxygen dependence, CO2 levels, cardiac valve function, liver and spleen size, and growth velocity were assessed to evaluate response to therapy. rhGUS infusions were well tolerated. No serious adverse events (SAEs) or IARs were observed. After initiation of rhGUS infusions, the patient's uGAG excretion decreased by more than 50%. Liver and spleen size were reduced within 2 weeks of the first infusion and reached normal size by 24 weeks. Pulmonary function appeared to improve during the course of treatment based on reduced changes in ETCO2 after off-ventilator challenges and a reduced oxygen requirement. The patient regained the ability to eat orally, gained weight, and his energy and activity levels increased. Over 24 weeks, treatment with every-other-week infusions of rhGUS was well tolerated with no SAEs, IARs, or hypersensitivity reactions and was associated with measurable improvement in objective clinical measures and quality of life.

  • Mutations and polymorphisms in GUSB gene in mucopolysaccharidosis VII (Sly Syndrome).
    Human Mutation, 2009
    Co-Authors: Shunji Tomatsu, Adriana M. Montaño, Vu Chi Dung, Jeffrey H. Grubb, William S. Sly
    Abstract:

    Mucopolysaccharidosis VII (MPS VII; Sly Syndrome) is an autosomal recessive disorder caused by a deficiency of beta-glucuronidase (GUS, EC 3.2.1.31; GUSB). GUS is required to degrade glycosaminoglycans (GAGs), including heparan sulfate (HS), dermatan sulfate (DS), and chondroitin-4,6-sulfate (CS). Accumulation of undegraded GAGs in lysosomes of affected tissues leads to mental retardation, short stature, hepatosplenomegaly, bone dysplasia, and hydrops fetalis. We summarize information on the 49 unique, disease-causing mutations determined so far in the GUS gene, including nine novel mutations (eight missense and one splice-site). This heterogeneity in GUS gene mutations contributes to the extensive clinical variability among patients with MPS VII. One pseudodeficiency allele, one polymorphism causing an amino acid change, and one silent variant in the coding region are also described. Among the 103 analyzed mutant alleles, missense mutations accounted for 78.6%; nonsense mutations, 12.6%; deletions, 5.8%; and splice-site mutations, 2.9%. Transitional mutations at CpG dinucleotides made up 40.8% of all the described mutations. The five most frequent mutations (accounting for 44/103 alleles) were exonic point mutations, p.L176F, p.R357X, p.P408S, p.P415L, and p.A619 V. Genotype/phenotype correlation was attempted by correlating the effects of certain missense mutations or enzyme activity and stability within phenotypes. These were in turn correlated with the location of the mutation in the tertiary structure of GUS. A total of seven murine, one feline, and one canine model of MPS VII have been characterized for phenotype and genotype.

  • PCR-Based Restriction Fragment Length Polymorphism And Haplotype of The Most Common Mutation L176F in The β-Glucuronidase Gene
    Genetic testing, 2007
    Co-Authors: M. Rafiq Islam, Gul N. Shah, William S. Sly
    Abstract:

    Mucopolysaccharidosis type VII or Sly Syndrome is an autosomal recessive disorder of glycosaminoglycan storage leading to variable clinical symptoms, such as hepatosplenomegaly, bone deformities, hearing loss, corneal opacities, mental retardation, and hydrops fetalis in affected individuals. The disease is caused by approximately 40 different mutations in the beta-glucuronidase gene. Detection of the most common mutation L176F by single-strand conformation polymorphism (SSCP) was not always successful. Although DNA sequencing followed by PCR amplification can easily detect this mutation, accessibility to a DNA sequencer or useful reagents in the sequencing procedure is not readily available in many countries. A PCR-based restriction fragment length polymorphism (RFLP) developed in this report would allow rapid and easier detection of this mutation for screening new patients or neonates of heterozygous parents. Analysis of intragenic polymorphic sites in the L176F patients identified two distinct alleles; the predominant one probably originated in Spain.

  • Active site mutant transgene confers tolerance to human β-glucuronidase without affecting the phenotype of MPS VII mice
    Proceedings of the National Academy of Sciences of the United States of America, 2001
    Co-Authors: William S. Sly, Carole Vogler, Shunji Tomatsu, Jeffrey H. Grubb, Mi Zhou, Jinxing Jiang, Xiao Yan Zhou, Elizabeth M. Snella
    Abstract:

    Mucopolysaccharidosis type VII (MPS VII; Sly Syndrome) is an autosomal recessive lysosomal storage disorder due to an inherited deficiency of β-glucuronidase. A naturally occurring mouse model for this disease was discovered at The Jackson Laboratory and shown to be due to homozygosity for a 1-bp deletion in exon 10 of the gus gene. The murine model MPS VII (gusmps/mps) has been very well characterized and used extensively to evaluate experimental strategies for lysosomal storage diseases, including bone marrow transplantation, enzyme replacement therapy, and gene therapy. To enhance the value of this model for enzyme and gene therapy, we produced a transgenic mouse expressing the human β-glucuronidase cDNA with an amino acid substitution at the active site nucleophile (E540A) and bred it onto the MPS VII (gusmps/mps) background. We demonstrate here that the mutant mice bearing the active site mutant human transgene retain the clinical, morphological, biochemical, and histopathological characteristics of the original MPS VII (gusmps/mps) mouse. However, they are now tolerant to immune challenge with human β-glucuronidase. This “tolerant MPS VII mouse model” should be useful for preclinical trials evaluating the effectiveness of enzyme and/or gene therapy with the human gene products likely to be administered to human patients with MPS VII.

  • Enzyme replacement therapy for murine mucopolysaccharidosis type VII leads to improvements in behavior and auditory function.
    The Journal of clinical investigation, 1998
    Co-Authors: Lynn H. O'connor, Carole Vogler, William S. Sly, Jeffrey H. Grubb, Lawrence C. Erway, Andrew Nicholes, S W Holmberg, B Levy, Mark S. Sands
    Abstract:

    Mucopolysaccharidosis type VII (MPS VII; Sly Syndrome) is one of a group of lysosomal storage diseases that share many clinical features, including mental retardation and hearing loss. Lysosomal storage in neurons of the brain and the associated behavioral abnormalities characteristic of a murine model of MPS VII have not been shown to be corrected by either bone marrow transplantation or gene therapy. However, intravenous injections of recombinant beta-glucuronidase initiated at birth reduce the pathological evidence of disease in MPS VII mice. In this study we present evidence that enzyme replacement initiated at birth improved the behavioral performance and reduced hearing loss in MPS VII mice. Enzyme-treated MPS VII mice performed similarly to normal mice and significantly better than mock- treated MPS VII mice in every phase of the Morris Water Maze test. In addition, the auditory function of treated MPS VII mice was dramatically improved, and was indistinguishable from normal mice. These data indicate that some of the learning, memory, and hearing deficits can be prevented in MPS VII mice if enzyme replacement therapy is initiated early in life. These data also provide functional correlates to the biochemical and histopathological improvements observed after enzyme replacement therapy.

Shunji Tomatsu - One of the best experts on this subject based on the ideXlab platform.

  • Mutations and polymorphisms in GUSB gene in mucopolysaccharidosis VII (Sly Syndrome).
    Human Mutation, 2009
    Co-Authors: Shunji Tomatsu, Adriana M. Montaño, Vu Chi Dung, Jeffrey H. Grubb, William S. Sly
    Abstract:

    Mucopolysaccharidosis VII (MPS VII; Sly Syndrome) is an autosomal recessive disorder caused by a deficiency of beta-glucuronidase (GUS, EC 3.2.1.31; GUSB). GUS is required to degrade glycosaminoglycans (GAGs), including heparan sulfate (HS), dermatan sulfate (DS), and chondroitin-4,6-sulfate (CS). Accumulation of undegraded GAGs in lysosomes of affected tissues leads to mental retardation, short stature, hepatosplenomegaly, bone dysplasia, and hydrops fetalis. We summarize information on the 49 unique, disease-causing mutations determined so far in the GUS gene, including nine novel mutations (eight missense and one splice-site). This heterogeneity in GUS gene mutations contributes to the extensive clinical variability among patients with MPS VII. One pseudodeficiency allele, one polymorphism causing an amino acid change, and one silent variant in the coding region are also described. Among the 103 analyzed mutant alleles, missense mutations accounted for 78.6%; nonsense mutations, 12.6%; deletions, 5.8%; and splice-site mutations, 2.9%. Transitional mutations at CpG dinucleotides made up 40.8% of all the described mutations. The five most frequent mutations (accounting for 44/103 alleles) were exonic point mutations, p.L176F, p.R357X, p.P408S, p.P415L, and p.A619 V. Genotype/phenotype correlation was attempted by correlating the effects of certain missense mutations or enzyme activity and stability within phenotypes. These were in turn correlated with the location of the mutation in the tertiary structure of GUS. A total of seven murine, one feline, and one canine model of MPS VII have been characterized for phenotype and genotype.

  • to human and mouse β-glucuronidase
    2006
    Co-Authors: Shunji Tomatsu, Carole Vogler, Jeffrey H. Grubb, Kazuko Sukegawa, Koji O. Orii, Elizabeth M. Snella, Monica A. Gutierrez, Tatiana Dieter, Christopher C. Holden, Naomi Kondo
    Abstract:

    Mucopolysaccharidosis VII (MPS VII, Sly Syndrome) is an autosomal recessive lysosomal storage disease caused by β-glucuronidase (GUS) deficiency. A naturally occurring mouse model of that disease has been very useful for studying experimental approaches to therapy. However, immune responses can complicate evaluation of the long-term benefits of enzyme replacement or gene therapy delivered to adult MPS VII mice. To make this model useful for studying the long-term effectiveness and side effects of experimental therapies delivered to adult mice, we developed a new MPS VII mouse model, which is tolerant to both human and murine GUS. To achieve this, we used homologous recombination to introduce simultaneouSly a human cDNA transgene expressing inactive human GUS into intron 9 of the murine Gus gene and a targeted active site mutation (E536A) into the adjacent exon 10. When the heterozygote products of germline transmission were bred to homozygosity, the homozygous mice expressed no GUS enzyme activity but expressed inactive human GUS protein highly and were tolerant to immune challenge with human enzyme. Expression of the mutant murine Gus gene was reduced to about 10% of normal levels, but the inactive murine GUS enzyme also conferred tolerance to murine GUS. This MPS VII mouse model should be useful to evaluate therapeutic responses in adult mice receiving repetitive doses of enzyme or mice receiving gene therapy as adults. Heterozygotes expressed only 9.5–26% of wild-type levels of murine GUS instead of the expected 50%, indicating a dominant-negative effect of the mutant enzyme monomers on the activity of GUS tetramers in different tissues. Corrective gene therapy in this model should provide high enough levels of expression of normal GUS monomers to overcome the dominant negative effect of mutant monomers on newly synthesized GUS tetramers in most tissues.

  • Production of MPS VII mouse (Gustm(hE540A.mE536A)Sly) doubly tolerant to human and mouse β-glucuronidase
    Human molecular genetics, 2003
    Co-Authors: Shunji Tomatsu, Carole Vogler, Jeffrey H. Grubb, Kazuko Sukegawa, Koji O. Orii, Elizabeth M. Snella, Monica A. Gutierrez, Tatiana Dieter, Christopher C. Holden, Tadao Orii
    Abstract:

    Mucopolysaccharidosis VII (MPS VII, Sly Syndrome) is an autosomal recessive lysosomal storage disease caused by β-glucuronidase (GUS) deficiency. A naturally occurring mouse model of that disease has been very useful for studying experimental approaches to therapy. However, immune responses can complicate evaluation of the long-term benefits of enzyme replacement or gene therapy delivered to adult MPS VII mice. To make this model useful for studying the long-term effectiveness and side effects of experimental therapies delivered to adult mice, we developed a new MPS VII mouse model, which is tolerant to both human and murine GUS. To achieve this, we used homologous recombination to introduce simultaneouSly a human cDNA transgene expressing inactive human GUS into intron 9 of the murine Gus gene and a targeted active site mutation (E536A) into the adjacent exon 10. When the heterozygote products of germline transmission were bred to homozygosity, the homozygous mice expressed no GUS enzyme activity but expressed inactive human GUS protein highly and were tolerant to immune challenge with human enzyme. Expression of the mutant murine Gus gene was reduced to about 10% of normal levels, but the inactive murine GUS enzyme also conferred tolerance to murine GUS. This MPS VII mouse model should be useful to evaluate therapeutic responses in adult mice receiving repetitive doses of enzyme or mice receiving gene therapy as adults. Heterozygotes expressed only 9.5–26% of wild-type levels of murine GUS instead of the expected 50%, indicating a dominant-negative effect of the mutant enzyme monomers on the activity of GUS tetramers in different tissues. Corrective gene therapy in this model should provide high enough levels of expression of normal GUS monomers to overcome the dominant negative effect of mutant monomers on newly synthesized GUS tetramers in most tissues.

  • Missense models [Gustm(E536A)Sly, Gustm(E536Q)Sly, and Gustm(L175F)Sly] of murine mucopolysaccharidosis type VII produced by targeted mutagenesis.
    Proceedings of the National Academy of Sciences of the United States of America, 2002
    Co-Authors: Shunji Tomatsu, Carole Vogler, Jeffrey H. Grubb, Kazuko Sukegawa, Tadao Orii, Koji O. Orii, Elizabeth M. Snella, Monica A. Gutierrez, Tatiana Dieter, Naomi Kondo
    Abstract:

    Human mucopolysaccharidosis VII (MPS VII, Sly Syndrome) results from a deficiency of β-glucuronidase (GUS) and has been associated with a wide range in severity of clinical manifestations. To study missense mutant models of murine MPS VII with phenotypes of varying severity, we used targeted mutagenesis to produce E536A and E536Q, corresponding to active-site nucleophile replacements E540A and E540Q in human GUS, and L175F, corresponding to the most common human mutation, L176F. The E536A mouse had no GUS activity in any tissue and displayed a severe phenotype like that of the originally described MPS VII mice carrying a deletion mutation (gusmps/mps). E536Q and L175F mice had low levels of residual activity and milder phenotypes. All three mutant MPS models showed progressive lysosomal storage in many tissues but had different rates of accumulation. The amount of urinary glycosaminoglycan excretion paralleled the clinical severity, with urinary glycosaminoglycans remarkably higher in E536A mice than in E536Q or L175F mice. Molecular analysis showed that the Gus mRNA levels were quantitatively similar in the three mutant mouse strains and normal mice. These mouse models, which mimic different clinical phenotypes of human MPS VII, should be useful in studying pathogenesis and also provide useful models for studying enzyme replacement therapy and targeted correction of missense mutations.

  • Production of MPS VII mouse (Gustm(hE540AmE536A)Sly) doubly tolerant to human and mouse b-glucuronidase
    2002
    Co-Authors: Shunji Tomatsu, Carole Vogler, Jeffrey H. Grubb, Koji O. Orii, Elizabeth M. Snella, Monica Gutierrez, Tatiana Dieterchristopher, C. Holden, Kazuko Sukegawatadao, Oriinaomi Kondowilliam
    Abstract:

    Mucopolysaccharidosis VII (MPS VII, Sly Syndrome) is an autosomal recessive lysosomal storage disease caused by b-glucuronidase (GUS) deficiency. A naturally occurring mouse model of that disease has been very useful for studying experimental approaches to therapy. However, immune responses can complicate evaluation of the long-term benefits of enzyme replacement or gene therapy delivered to adult MPS VII mice. To make this model useful for studying the long-term effectiveness and side effects of experimental therapies delivered to adult mice, we developed a new MPS VII mouse model, which is tolerant to both human and murine GUS. To achieve this, we used homologous recombination to introduce simultaneouSly a human cDNA transgene expressing inactive human GUS into intron 9 of the murine Gus gene and a targeted active site mutation (E536A) into the adjacent exon 10. When the heterozygote products of germline transmission were bred to homozygosity, the homozygous mice expressed no GUS enzyme activity but expressed inactive human GUS protein highly and were tolerant to immune challenge with human enzyme. Expression of the mutant murine Gus gene was reduced to about 10 % of normal levels, but the inactive murine GUS enzyme also conferred tolerance to murine GUS. This MPS VII mouse model should be useful to evaluate therapeutic responses in adult mice receiving repetitive doses of enzyme or mice receiving gene therapy as adults. Heterozygotes expressed only 9.5–26 % of wild-type levels of murine GUS instead of the expected 50%

Mark S. Sands - One of the best experts on this subject based on the ideXlab platform.

  • Inner ear pathology in the mucopolysaccharidosis VII mouse.
    Hearing Research, 2002
    Co-Authors: Kevin K Ohlemiller, Anne K Hennig, Jaclynn M Lett, Arnold F Heidbreder, Mark S. Sands
    Abstract:

    Mucopolysaccharidosis type VII (MPS VII, Sly Syndrome) is caused by dysfunction of the acid hydrolase β-D-glucuronidase. The defect results in the accumulation of incompletely degraded glycosaminoglycans within lysosomes of a wide array of cell types. MPS VII is associated with mixed (conductive and sensorineural) hearing loss, vision defects, shortened stature, mental retardation and decreased lifespan. Whether the sensorineural component of hearing loss in MPS VII involves degeneration of cochlear sensory cells is not yet clear. The MPS VII mouse resembles its human counterpart in all major aspects, and has been the focus of extensive research seeking to correct MPS VII and other lysosomal storage diseases. The value of potential treatments for this hearing loss can be determined only if cochlear pathology in this model is well characterized. We examined threshold sensitivity, frequency tuning, hair cell density and the appearance of the cochlea and vestibular organs in MPS VII mice ranging from 1.0 to 7.5 months of age. At all ages, lysosomal storage is pronounced within cells of spiral limbus, spiral prominence, spiral ligament and glial cells, but not within organ of Corti, stria vascularis, or neurons. Within the vestibular maculae and cristae, both hair cells and supporting cells also show lysosomal storage. Although hearing thresholds are never normal, reduction in the sharpness of frequency tuning is not apparent until 2.5 months of age, suggesting that the sensorineural component of hearing loss begins in adulthood. No evidence was found for cell loss within the organ of Corti, or any other structure, however. Our results suggest that sensorineural hearing loss in the MPS VII mouse is not caused by degeneration, but may arise from alterations in mass and stiffness of cochlear structures or impaired sensory cell function. They also indicate a possible vestibular component in MPS VII.

  • Inner ear pathology in the mucopolysaccharidosis VII mouse.
    Hearing research, 2002
    Co-Authors: Kevin K Ohlemiller, Anne K Hennig, Jaclynn M Lett, Arnold F Heidbreder, Mark S. Sands
    Abstract:

    Mucopolysaccharidosis type VII (MPS VII, Sly Syndrome) is caused by dysfunction of the acid hydrolase beta-D-glucuronidase. The defect results in the accumulation of incompletely degraded glycosaminoglycans within lysosomes of a wide array of cell types. MPS VII is associated with mixed (conductive and sensorineural) hearing loss, vision defects, shortened stature, mental retardation and decreased lifespan. Whether the sensorineural component of hearing loss in MPS VII involves degeneration of cochlear sensory cells is not yet clear. The MPS VII mouse resembles its human counterpart in all major aspects, and has been the focus of extensive research seeking to correct MPS VII and other lysosomal storage diseases. The value of potential treatments for this hearing loss can be determined only if cochlear pathology in this model is well characterized. We examined threshold sensitivity, frequency tuning, hair cell density and the appearance of the cochlea and vestibular organs in MPS VII mice ranging from 1.0 to 7.5 months of age. At all ages, lysosomal storage is pronounced within cells of spiral limbus, spiral prominence, spiral ligament and glial cells, but not within organ of Corti, stria vascularis, or neurons. Within the vestibular maculae and cristae, both hair cells and supporting cells also show lysosomal storage. Although hearing thresholds are never normal, reduction in the sharpness of frequency tuning is not apparent until 2.5 months of age, suggesting that the sensorineural component of hearing loss begins in adulthood. No evidence was found for cell loss within the organ of Corti, or any other structure, however. Our results suggest that sensorineural hearing loss in the MPS VII mouse is not caused by degeneration, but may arise from alterations in mass and stiffness of cochlear structures or impaired sensory cell function. They also indicate a possible vestibular component in MPS VII.

  • Murine Mucopolysaccharidosis VII: Impact of Therapies on the Phenotype, Clinical Course, and Pathology in a Model of a Lysosomal Storage Disease
    Pediatric and Developmental Pathology, 2001
    Co-Authors: Carole Vogler, Mark S. Sands, Jane Barker, Beth Levy, Nancy Galvin
    Abstract:

    The mucopolysaccharidoses are a group of lysosomal storage diseases caused by deficiency of an enzyme required for the normal degradation of glycosaminoglycans. Patients with mucopolysaccharidosis typically have widespread lysosomal storage, skeletal and central nervous system disease, and hepatosplenomegaly. Some patients with mucopolysaccharidosis may benefit from enzyme replacement therapy or bone marrow transplantation. Animal models of mucopolysaccharidosis have proven valuable for the evaluation of the effectiveness of potential treatments for patients with lysosomal storage disease. A murine model of MPS VII (Sly Syndrome) has proven particularly useful because of its well-defined genetics and its well-characterized clinical, pathologic, and biochemical alterations, which resemble those seen in patients with mucopolysaccharidosis. Correction of these alterations forms the basis for evaluation of the effectiveness of novel treatments. A wide range of therapies have been tested using this model, including enzyme replacement therapy, bone marrow, stem cell, and neural progenitor cell transplantation, and a variety of viral-mediated gene therapies. The inferences drawn from these therapeutic studies using the murine MPS VII model are likely generalizable to other lysosomal storage diseases.

  • intracisternal a particle element transposition into the murine beta glucuronidase gene correlates with loss of enzyme activity a new model for beta glucuronidase deficiency in the c3h mouse
    Molecular and Cellular Biology, 1998
    Co-Authors: B Gwynn, Mark S. Sands, Kira Lueders, Edward H Birkenmeier
    Abstract:

    The severity of human mucopolysaccharidosis type VII (MPS VII), or Sly Syndrome, depends on the relative activity of the enzyme β-glucuronidase. Loss of β-glucuronidase activity can cause hydrops fetalis, with in utero or postnatal death of the patient. In this report, we show that β-glucuronidase activity is not detectable by a standard fluorometric assay in C3H/HeOuJ (C3H) mice homozygous for a new mutation, gusmps2J. These gusmps2J/gusmps2J mice are born and survive much longer than the previouSly characterized β-glucuronidase-null B6.C-H-2bm1/ByBir-gusmps (gusmps/gusmps) mice. Northern blot analysis of liver from gusmps2J/gusmps2J mice demonstrates a 750-bp reduction in size of β-glucuronidase mRNA. A 5.4-kb insertion in the Gus-sh nucleotide sequence from these mice was localized by Southern blot analysis to intron 8. The ends of the inserted sequences were cloned by inverse PCR and revealed an intracisternal A-particle (IAP) element inserted near the 3′ end of the intron. The sequence of the long terminal repeat (LTR) regions of the IAP most closely matches that of a composite LTR found in transposed IAPs previouSly identified in the C3H strain. The inserted IAP may contribute to diminished β-glucuronidase activity either by interfering with transcription or by destabilizing the message. The resulting phenotype is much less severe than that previouSly described in the gusmps/gusmps mouse and provides an opportunity to study MPS VII on a genetic background that clearly modulates disease severity.

  • Murine mucopolysaccharidosis type VII: The impact of therapies on the clinical course and pathology in a murine model of lysosomal storage disease
    Journal of Inherited Metabolic Disease, 1998
    Co-Authors: C. Vogler, Mark S. Sands, Jane Barker, Nancy Galvin, B Levy, C. Thorpe, W. S. Sly
    Abstract:

    Murine mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a recessively inherited deficiency of the lysosomal enzyme β-glucuronidase. Affected mice have clinical, biochemical and pathological findings similar to those seen in humans with MPS VII (Sly Syndrome), including growth retardation, facial dysmorphism, deafness, behavioural deficits and widespread glycosaminoglycan storage in lysosomes in the viscera, skeleton and brain. This mouse model is a useful tool for the evaluation of the effectiveness and experimental therapies for the MPS disorders. Syngeneic bone marrow transplantation performed in newborn MPS VII animals – before clinical evidence of disease is pronounced – prolongs life, improves hearing and bone growth, and prevents lysosomal storage in many sites, but does not correct the central nervous system disease. Enzyme therapy with β-glucuronidase from the first days of life does reduce lysosomal storage in the brain in murine MPS VII. The enzyme-replaced mice also have reduced visceral lysosomal storage, impressive normalization of their phenotype and an improved life span. The effectiveness of gene therapy for the treatment of lysosomal storage disease has also been tested using the MPS VII model. When transplanted into MPS VII mice, syngeneic haematopoietic stem cells or mouse skin fibroblasts infected with retrovirus expressing β-glucuronidase decreased storage, but only in the liver and spleen. Injection of an adenovirus vector expressing β-glucuronidase into the vitreous of the MPS VII mice reduced storage in the retinal pigment epithelium and corneal endothelium. Intravenous administration of the adenovirus vector transduced with the β-glucuronidase gene reduced liver and spleen storage and, when instilled into the cerebral ventricles, this viral vector caused β-glucuronidase production in epithelial cells lining the ventricles. Recently, retroviral vector-corrected MPS VII fibroblasts secreting high levels of β-glucuronidase were engrafted directly into the brains of adult MPS VII mice with resultant reduction in storage in neurons and glia adjacent to the grafts. Future efforts aimed at prolonging expression of the β-glucuronidase gene by viral vectors and more precisely directing the therapeutic effect to the skeleton and brain will be important in optimizing treatments for murine MPS VII and extending the results of such therapies to humans with MPS.

Jeffrey H. Grubb - One of the best experts on this subject based on the ideXlab platform.

  • Mutations and polymorphisms in GUSB gene in mucopolysaccharidosis VII (Sly Syndrome).
    Human Mutation, 2009
    Co-Authors: Shunji Tomatsu, Adriana M. Montaño, Vu Chi Dung, Jeffrey H. Grubb, William S. Sly
    Abstract:

    Mucopolysaccharidosis VII (MPS VII; Sly Syndrome) is an autosomal recessive disorder caused by a deficiency of beta-glucuronidase (GUS, EC 3.2.1.31; GUSB). GUS is required to degrade glycosaminoglycans (GAGs), including heparan sulfate (HS), dermatan sulfate (DS), and chondroitin-4,6-sulfate (CS). Accumulation of undegraded GAGs in lysosomes of affected tissues leads to mental retardation, short stature, hepatosplenomegaly, bone dysplasia, and hydrops fetalis. We summarize information on the 49 unique, disease-causing mutations determined so far in the GUS gene, including nine novel mutations (eight missense and one splice-site). This heterogeneity in GUS gene mutations contributes to the extensive clinical variability among patients with MPS VII. One pseudodeficiency allele, one polymorphism causing an amino acid change, and one silent variant in the coding region are also described. Among the 103 analyzed mutant alleles, missense mutations accounted for 78.6%; nonsense mutations, 12.6%; deletions, 5.8%; and splice-site mutations, 2.9%. Transitional mutations at CpG dinucleotides made up 40.8% of all the described mutations. The five most frequent mutations (accounting for 44/103 alleles) were exonic point mutations, p.L176F, p.R357X, p.P408S, p.P415L, and p.A619 V. Genotype/phenotype correlation was attempted by correlating the effects of certain missense mutations or enzyme activity and stability within phenotypes. These were in turn correlated with the location of the mutation in the tertiary structure of GUS. A total of seven murine, one feline, and one canine model of MPS VII have been characterized for phenotype and genotype.

  • to human and mouse β-glucuronidase
    2006
    Co-Authors: Shunji Tomatsu, Carole Vogler, Jeffrey H. Grubb, Kazuko Sukegawa, Koji O. Orii, Elizabeth M. Snella, Monica A. Gutierrez, Tatiana Dieter, Christopher C. Holden, Naomi Kondo
    Abstract:

    Mucopolysaccharidosis VII (MPS VII, Sly Syndrome) is an autosomal recessive lysosomal storage disease caused by β-glucuronidase (GUS) deficiency. A naturally occurring mouse model of that disease has been very useful for studying experimental approaches to therapy. However, immune responses can complicate evaluation of the long-term benefits of enzyme replacement or gene therapy delivered to adult MPS VII mice. To make this model useful for studying the long-term effectiveness and side effects of experimental therapies delivered to adult mice, we developed a new MPS VII mouse model, which is tolerant to both human and murine GUS. To achieve this, we used homologous recombination to introduce simultaneouSly a human cDNA transgene expressing inactive human GUS into intron 9 of the murine Gus gene and a targeted active site mutation (E536A) into the adjacent exon 10. When the heterozygote products of germline transmission were bred to homozygosity, the homozygous mice expressed no GUS enzyme activity but expressed inactive human GUS protein highly and were tolerant to immune challenge with human enzyme. Expression of the mutant murine Gus gene was reduced to about 10% of normal levels, but the inactive murine GUS enzyme also conferred tolerance to murine GUS. This MPS VII mouse model should be useful to evaluate therapeutic responses in adult mice receiving repetitive doses of enzyme or mice receiving gene therapy as adults. Heterozygotes expressed only 9.5–26% of wild-type levels of murine GUS instead of the expected 50%, indicating a dominant-negative effect of the mutant enzyme monomers on the activity of GUS tetramers in different tissues. Corrective gene therapy in this model should provide high enough levels of expression of normal GUS monomers to overcome the dominant negative effect of mutant monomers on newly synthesized GUS tetramers in most tissues.

  • Production of MPS VII mouse (Gustm(hE540A.mE536A)Sly) doubly tolerant to human and mouse β-glucuronidase
    Human molecular genetics, 2003
    Co-Authors: Shunji Tomatsu, Carole Vogler, Jeffrey H. Grubb, Kazuko Sukegawa, Koji O. Orii, Elizabeth M. Snella, Monica A. Gutierrez, Tatiana Dieter, Christopher C. Holden, Tadao Orii
    Abstract:

    Mucopolysaccharidosis VII (MPS VII, Sly Syndrome) is an autosomal recessive lysosomal storage disease caused by β-glucuronidase (GUS) deficiency. A naturally occurring mouse model of that disease has been very useful for studying experimental approaches to therapy. However, immune responses can complicate evaluation of the long-term benefits of enzyme replacement or gene therapy delivered to adult MPS VII mice. To make this model useful for studying the long-term effectiveness and side effects of experimental therapies delivered to adult mice, we developed a new MPS VII mouse model, which is tolerant to both human and murine GUS. To achieve this, we used homologous recombination to introduce simultaneouSly a human cDNA transgene expressing inactive human GUS into intron 9 of the murine Gus gene and a targeted active site mutation (E536A) into the adjacent exon 10. When the heterozygote products of germline transmission were bred to homozygosity, the homozygous mice expressed no GUS enzyme activity but expressed inactive human GUS protein highly and were tolerant to immune challenge with human enzyme. Expression of the mutant murine Gus gene was reduced to about 10% of normal levels, but the inactive murine GUS enzyme also conferred tolerance to murine GUS. This MPS VII mouse model should be useful to evaluate therapeutic responses in adult mice receiving repetitive doses of enzyme or mice receiving gene therapy as adults. Heterozygotes expressed only 9.5–26% of wild-type levels of murine GUS instead of the expected 50%, indicating a dominant-negative effect of the mutant enzyme monomers on the activity of GUS tetramers in different tissues. Corrective gene therapy in this model should provide high enough levels of expression of normal GUS monomers to overcome the dominant negative effect of mutant monomers on newly synthesized GUS tetramers in most tissues.

  • Missense models [Gustm(E536A)Sly, Gustm(E536Q)Sly, and Gustm(L175F)Sly] of murine mucopolysaccharidosis type VII produced by targeted mutagenesis.
    Proceedings of the National Academy of Sciences of the United States of America, 2002
    Co-Authors: Shunji Tomatsu, Carole Vogler, Jeffrey H. Grubb, Kazuko Sukegawa, Tadao Orii, Koji O. Orii, Elizabeth M. Snella, Monica A. Gutierrez, Tatiana Dieter, Naomi Kondo
    Abstract:

    Human mucopolysaccharidosis VII (MPS VII, Sly Syndrome) results from a deficiency of β-glucuronidase (GUS) and has been associated with a wide range in severity of clinical manifestations. To study missense mutant models of murine MPS VII with phenotypes of varying severity, we used targeted mutagenesis to produce E536A and E536Q, corresponding to active-site nucleophile replacements E540A and E540Q in human GUS, and L175F, corresponding to the most common human mutation, L176F. The E536A mouse had no GUS activity in any tissue and displayed a severe phenotype like that of the originally described MPS VII mice carrying a deletion mutation (gusmps/mps). E536Q and L175F mice had low levels of residual activity and milder phenotypes. All three mutant MPS models showed progressive lysosomal storage in many tissues but had different rates of accumulation. The amount of urinary glycosaminoglycan excretion paralleled the clinical severity, with urinary glycosaminoglycans remarkably higher in E536A mice than in E536Q or L175F mice. Molecular analysis showed that the Gus mRNA levels were quantitatively similar in the three mutant mouse strains and normal mice. These mouse models, which mimic different clinical phenotypes of human MPS VII, should be useful in studying pathogenesis and also provide useful models for studying enzyme replacement therapy and targeted correction of missense mutations.

  • Production of MPS VII mouse (Gustm(hE540AmE536A)Sly) doubly tolerant to human and mouse b-glucuronidase
    2002
    Co-Authors: Shunji Tomatsu, Carole Vogler, Jeffrey H. Grubb, Koji O. Orii, Elizabeth M. Snella, Monica Gutierrez, Tatiana Dieterchristopher, C. Holden, Kazuko Sukegawatadao, Oriinaomi Kondowilliam
    Abstract:

    Mucopolysaccharidosis VII (MPS VII, Sly Syndrome) is an autosomal recessive lysosomal storage disease caused by b-glucuronidase (GUS) deficiency. A naturally occurring mouse model of that disease has been very useful for studying experimental approaches to therapy. However, immune responses can complicate evaluation of the long-term benefits of enzyme replacement or gene therapy delivered to adult MPS VII mice. To make this model useful for studying the long-term effectiveness and side effects of experimental therapies delivered to adult mice, we developed a new MPS VII mouse model, which is tolerant to both human and murine GUS. To achieve this, we used homologous recombination to introduce simultaneouSly a human cDNA transgene expressing inactive human GUS into intron 9 of the murine Gus gene and a targeted active site mutation (E536A) into the adjacent exon 10. When the heterozygote products of germline transmission were bred to homozygosity, the homozygous mice expressed no GUS enzyme activity but expressed inactive human GUS protein highly and were tolerant to immune challenge with human enzyme. Expression of the mutant murine Gus gene was reduced to about 10 % of normal levels, but the inactive murine GUS enzyme also conferred tolerance to murine GUS. This MPS VII mouse model should be useful to evaluate therapeutic responses in adult mice receiving repetitive doses of enzyme or mice receiving gene therapy as adults. Heterozygotes expressed only 9.5–26 % of wild-type levels of murine GUS instead of the expected 50%