Home  About us  Contact
 

Lysosomal Storage (lysosomal + storage)

Distribution by Scientific Domains
Life Sciences71%
Medical Sciences28%

Terms modified by Lysosomal Storage

  • lysosomal storage disease
    		•
  • lysosomal storage disorder
    		•
  • lysosomal storage disorders
    		•

    Selected Abstracts

    Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA),,

    HUMAN MUTATION, Issue 5 2008
    Kathleen S. Hruska
    Abstract Gaucher disease (GD) is an autosomal recessive disorder caused by the deficiency of glucocerebrosidase, a lysosomal enzyme that catalyses the hydrolysis of the glycolipid glucocerebroside to ceramide and glucose. Lysosomal storage of the substrate in cells of the reticuloendothelial system leads to multisystemic manifestations, including involvement of the liver, spleen, bone marrow, lungs, and nervous system. Patients with GD have highly variable presentations and symptoms that, in many cases, do not correlate well with specific genotypes. Almost 300 unique mutations have been reported in the glucocerebrosidase gene (GBA), with a distribution that spans the gene. These include 203 missense mutations, 18 nonsense mutations, 36 small insertions or deletions that lead to either frameshifts or in-frame alterations, 14 splice junction mutations, and 13 complex alleles carrying two or more mutations in cis. Recombination events with a highly homologous pseudogene downstream of the GBA locus also have been identified, resulting from gene conversion, fusion, or duplication. In this review we discuss the spectrum of GBA mutations and their distribution in the patient population, evolutionary conservation, clinical presentations, and how they may affect the structure and function of glucocerebrosidase. Hum Mutat 29(5), 567,583, 2008. Published 2008 Wiley-Liss, Inc. [source]

    Pathogenic mutations cause rapid degradation of lysosomal storage disease-related membrane protein CLN6,

    HUMAN MUTATION, Issue 2 2010
    Anna-Katherina Kurze
    Abstract One variant form of late infantile neuronal ceroid lipofuscinosis is an autosomal recessive inherited neurodegenerative lysosomal storage disorder caused by mutations in the CLN6gene. The function of the polytopic CLN6 membrane protein localized in the endoplasmic reticulum is unknown. Here we report on expression studies of three mutations (c.368G>A, c.460-462delATC, c.316insC) found in CLN6 patients predicted to affect transmembrane domain 3 (p.Gly123Asp), cytoplasmic loop 2 (p.Ile154del) or result in a truncated membrane protein (p.Arg106ProfsX26), respectively. The rate of synthesis and the stability of the mutant CLN6 proteins are reduced in a mutation-dependent manner. None of the mutations prevented the dimerization of the CLN6 polypeptides. The particularly rapid degradation of the p.Arg106ProfsX26 mutant which is identical with the mutation in the murine orthologue Cln6 gene in the nclf mouse model of the disease, can be strongly inhibited by proteasomal and partially by lysosomal protease inhibitors. Both degradative pathways seem to be sufficient to prevent the accumulation/aggregation of the mutant CLN6 polypeptides in the endoplasmic reticulum. © 2009 Wiley-Liss, Inc. [source]

    Molecular pathology of NEU1 gene in sialidosis,

    HUMAN MUTATION, Issue 5 2003
    Volkan Seyrantepe
    Abstract Lysosomal sialidase (EC 3.2.1.18) has a dual physiological function; it participates in intralysosomal catabolism of sialylated glycoconjugates and is involved in cellular immune response. Mutations in the sialidase gene NEU1, located on chromosome 6p21.3, result in autosomal recessive disorder, sialidosis, which is characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. Sialidosis type I is a milder, late-onset, normosomatic form of the disorder. Type I patients develop visual defects, myoclonus syndrome, cherry-red macular spots, ataxia, hyperreflexia, and seizures. The severe early-onset form, sialidosis type II, is also associated with dysostosis multiplex, Hurler-like phenotype, mental retardation, and hepatosplenomegaly. We summarize information on the 34 unique mutations determined so far in the sialidase gene, including four novel missense and one novel nonsense mutations found in two Czech and two French sialidosis patients. The analysis of sialidase mutations in sialidosis revealed considerable molecular heterogeneity, reflecting the diversity of clinical phenotypes that make molecular diagnosis difficult. The majority of sialidosis patients have had missense mutations, many of which have been expressed; their effects on activity, stability, intracellular localization, and supramolecular organization of sialidase were studied. A structural model of sialidase allowed us to localize mutations in the sialidase molecule and to predict their impact on the tertiary structure and biochemical properties of the enzyme. Hum Mutat 22:343,352, 2003. © 2003 Wiley-Liss, Inc. [source]

    Glycosphingolipid lysosomal storage diseases: therapy and pathogenesis

    NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 5 2002
    M. Jeyakumar
    Paediatric neurodegenerative diseases are frequently caused by inborn errors in glycosphingolipid (GSL) catabolism and are collectively termed the glycosphingolipidoses. GSL catabolism occurs in the lysosome and a defect in an enzyme involved in GSL degradation leads to the lysosomal storage of its substrate(s). GSLs are abundantly expressed in the central nervous system (CNS) and the disorders frequently have a progressive neurodegenerative course. Our understanding of pathogenesis in these diseases is incomplete and currently few options exist for therapy. In this review we discuss how mouse models of these disorders are providing insights into pathogenesis and also leading to progress in evaluating experimental therapies. [source]

    Correction of mucopolysaccharidosis type IIIA somatic and central nervous system pathology by lentiviral-mediated gene transfer

    THE JOURNAL OF GENE MEDICINE, Issue 9 2010
    Chantelle McIntyre
    Abstract Background The hallmark of lysosomal storage disorders (LSDs) is microscopically demonstrable lysosomal distension. In mucopolysaccharidosis type IIIA (MPS IIIA), this occurs as a result of an inherited deficiency of the lysosomal hydrolase sulphamidase. Consequently, heparan sulphate, a highly sulphated glycosaminoglycan, accumulates primarily within the cells of the reticulo-endothelial and monocyte-macrophage systems and, most importantly, neurones. Children affected by MPS IIIA experience a severe, progressive neuropathology that ultimately leads to death at around 15 years of age. Methods MPS IIIA pathology was addressed in a mouse model using two separate methods of therapeutic gene delivery. A lentiviral vector expressing murine sulphamidase was delivered to 6-week-old MPS IIIA affected mice either by intravenous injection, or by intraventricular infusion. Therapeutic outcomes were assessed 7 months after gene transfer. Results After intravenous gene delivery, liver sulphamidase was restored to approximately 30% of wild-type levels. The resultant widespread delivery of enzyme secreted from transduced cells to somatic tissues via the peripheral circulation corrected most somatic pathology. However, unlike an earlier study, central nervous system (CNS) pathology remained unchanged. Conversely, intraventricular gene delivery resulted in widespread sulphamidase gene delivery in (and reduced lysosomal storage throughout) the brain. Improvements in behaviour were observed in these mice, and interestingly, pathological urinary retention was prevented. Conclusions The CNS remains the last major barrier to effective therapy for children affected by LSDs. The blood,brain barrier (BBB) limits the uptake of lysosomal enzymes from the peripheral circulation into the CNS, making direct gene delivery to the brain a reasonable, albeit more challenging, therapeutic option. Future work will further assess the relative advantages of directly targeting the brain with somatic gene delivery with sulphamidase modified to increase the efficiency of transport across the BBB. Copyright © 2010 John Wiley & Sons, Ltd. [source]

    Autosomal Dominant Adult Neuronal Ceroid Lipofuscinosis: a Novel Form of NCL with Granular Osmiophilic Deposits without Palmitoyl Protein Thioesterase 1 Deficiency

    BRAIN PATHOLOGY, Issue 4 2003
    Peter C. G. Nijssen
    We describe the neuropathological and biochemical autopsy findings in 3 patients with autosomal dominant adult neuronal ceroid lipofuscinosis (ANCL, Parry type; MIM 162350), from a family with 6 affected individuals in 3 generations. Throughout the brain of these patients, there was abundant intraneuronal lysosomal storage of autofluorescent lipopigment granules. Striking loss of neurons in the substantia nigra was found. In contrast, little neuronal cell loss occurred in other cerebral areas, despite massive neuronal inclusions. Visceral storage was present in gut, liver, cardiomyocytes, skeletal muscle, and in the skin eccrine glands. The storage material showed highly variable immunoreactivity with antiserum against subunit c of mitochondrial ATP synthase, but uniform strong immunoreactivity for saposin D (sphingolipid activating protein D). Protein electrophoresis of isolated storage material revealed a major protein band of about 14 kDa, recognized in Western blotting by saposin D antiserum (but not subunit c of mitochondrial ATPase (SCMAS) antiserum). Electron microscopy showed ample intraneuronal granular osmiophilic deposits (GRODs), as occurs in CLN1 and congenital ovine NCL. These forms of NCL are caused by the deficiencies of palmitoyl protein thioesterase 1 and cathepsin D, respectively. However, activities of these enzymes were within normal range in our patients. Thus we propose that a gene distinct from the cathepsin D and CLN1-CLN8 genes is responsible for this autosomal dominant form of ANCL. [source]

    Enzyme replacement therapy with agalsidase alfa in a cohort of Italian patients with Anderson,Fabry disease: testing the effects with the Mainz Severity Score Index

    CLINICAL GENETICS, Issue 3 2008
    R Parini
    Anderson,Fabry disease (AFD) is a rare X-linked disorder caused by lysosomal storage of several glycosphingolipids, affecting virtually all organs and systems. Enzyme replacement therapy (ERT) for AFD has been available since 2001. Due to the highly variable nature of clinical manifestations in patients with AFD, it is very difficult to assess disease progression and the effects of therapy. We used the Mainz Severity Score Index (MSSI) as a measure of disease severity to study the effects of ERT in a population of 30 patients treated with agalsidase alfa for a median of 2.9 years (range, 1.0,6.2 years). Our data show that the MSSI captures the correlation between disease severity and both gender and age (1 , males performing worse than females at baseline and 2 , severity of diseases progresses with age in both sex). Furthermore, after at least 1 year of ERT, total MSSI scores were significantly lower than those at baseline (p < 0.001), suggesting a marked clinical improvement under ERT. In conclusion, the MSSI is a sensitive and useful tool for monitoring disease progression and assessing the effects of ERT in a population of patients from different treatment centres. [source]