Genetics of Lysosomal Storage Disorders and Counselling

Hopwood, John J.

doi:10.1002/9781118514672.ch4

Cited by 5 publications

(2 citation statements)

References 21 publications

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“…MPS disorders have significant phenotypic variability and, with the exception of MPS II, are autosomal recessive. 29 β-glu enzymatic activity deficiencies lead to primary accumulation of GAGs, and secondary accumulation of GM2 and GM3 gangliosides, which have been linked to neuroinflammation. While ERT has significantly improved the life of some LSD patients, no MPS VII-related pathology in the HD-GFP-and the HD-RIGIE-injected dog brains was assessed by a masked pathologist without knowledge of the genotype/treatment group using tissue that had been postfixed in paraformaldehyde, cryopreserved in sucrose, embedded, and cut into 10-μm-thick sections.…”

Section: Discussionmentioning

confidence: 99%

Corrective GUSB Transfer to the Canine Mucopolysaccharidosis VII Brain

Cubizolle¹,

Serratrice²,

Skander³

et al. 2014

Molecular Therapy

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Severe deficiency in lysosomal β-glucuronidase (β-glu) enzymatic activity results in mucopolysaccharidosis (MPS) VII, an orphan disease with symptoms often appearing in early childhood. Symptoms are variable, but many patients have multiple organ disorders including neurological defects. At the cellular level, deficiency in β-glu activity leads to abnormal accumulation of glycosaminoglycans (GAGs), and secondary accumulation of GM2 and GM3 gangliosides, which have been linked to neuroinflammation. There have been encouraging gene transfer studies in the MPS VII mouse brain, but this is the first study attempting the correction of the >200-fold larger and challenging canine MPS VII brain. Here, the efficacy of a helper-dependent (HD) canine adenovirus (CAV-2) vector harboring a human GUSB expression cassette (HD-RIGIE) in the MPS VII dog brain was tested. Vector genomes, β-glu activity, GAG content, lysosome morphology and neuropathology were analyzed and quantified. Our data demonstrated that CAV-2 vectors preferentially transduced neurons and axonal retrograde transport from the injection site to efferent regions was efficient. HD-RIGIE injections, associated with mild and transient immunosuppression, corrected neuropathology in injected and noninjected structures throughout the cerebrum. These data support the clinical evaluation of HD CAV-2 vectors to treat the neurological defects associated with MPS VII and possibly other neuropathic lysosomal storage diseases.

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Section: Discussionmentioning

confidence: 99%

Corrective GUSB Transfer to the Canine Mucopolysaccharidosis VII Brain

Cubizolle¹,

Serratrice²,

Skander³

et al. 2014

Molecular Therapy

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“…Defects in lysosomal function are common for example in Alzheimer's and Parkinson's diseases . There are over 50 inherited lysosomal storage disorders (LSDs) that result from mutations in a single lysosomal hydrolase or in a nonlysosomal protein important for the function of the lysosomes . Common for all LSDs is the impairment of hydrolysis and the result of it: the accumulation of undegraded material in lysosomes.…”

Section: Introductionmentioning

confidence: 99%

Is the bovine lysosomal phospholipase B-like protein an amidase?

et al. 2013

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The main function of lysosomal proteins is to degrade cellular macromolecules. We purified a novel lysosomal protein to homogeneity from bovine kidneys. By gene annotation, this protein is defined as a bovine phospholipase B-like protein 1 (bPLBD1) and, to better understand its biological function, we solved its structure at 1.9 Å resolution. We showed that bPLBD1 has uniform noncomplex-type N-glycosylation and that it localized to the lysosome. The first step in lysosomal protein transport, the initiation of mannose-6-phosphorylation by a N-acetylglucosamine-1-phosphotransferase, requires recognition of at least two distinct lysines on the protein surface. We identified candidate lysines by analyzing the structural and sequentially conserved N-glycosylation sites and lysines in bPLBD1 and in the homologous mouse PLBD2. Our model suggests that N408 is the primarily phosphorylated glycan, and K358 a key residue for N-acetylglucosamine-1-phosphotransferase recognition. Two other lysines, K334 and K342, provide the required second site for N-acetylglucosamine-1-phosphotransferase recognition. bPLBD1 is an N-terminal nucleophile (Ntn) hydrolase. By comparison with other Ntn-hydrolases, we conclude that the acyl moiety of PLBD1 substrate must be small to fit the putative binding pocket, whereas the space for the rest of the substrate is a large open cleft. Finally, as all the known substrates of Ntn-hydrolases have amide bonds, we suggest that bPLBD1 may be an amidase or peptidase instead of lipase, explaining the difficulty in finding a good substrate for any members of the PLBD family.

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