Lipoid Proteinosis: In Vivo and in Vitro Evidence for a Lysosomal Storage Disease

Abstract Beta (β)-glucosidase 2 (GBA2) is deficient in a form of human spastic paraplegia due to defects in GBA2 (SPG46). GBA2 was proposed as a modifier of Gaucher disease, a lysosomal storage disease resulting from deficient β-glucosidase 1; GBA1. Current GBA2 activity assays using artificial substrates incompletely model the activity encountered in vivo. We studied GBA2 activity, using lithocholic acid β-glucoside or glucosylceramide as natural β-glucosidase substrates in murine tissues or cultured patient fibroblasts with the pathologic genotypes: Gba1−/−; Gba2−/−; GBA1−/−; GBA2+/− and found expected and unexpected deviations from normal controls.

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Analysis of glucocerebrosidase activity using N-(1-[14C]hexanoyl)-d-erythro-glucosylsphingosine demonstrates a correlation between levels of residual enzyme activity and the type of Gaucher disease

Biochemical Journal ◽

10.1042/bj3030377 ◽

1994 ◽

Vol 303 (2) ◽

pp. 377-382 ◽

Cited By ~ 49

Author(s):

I Meivar-Levy ◽

M Horowitz ◽

A H Futerman

Keyword(s):

Enzyme Activity ◽

Lysosomal Storage Disease ◽

Gaucher Disease ◽

Storage Disease ◽

Acyl Chain ◽

Clinical Severity ◽

Residual Enzyme Activity ◽

Lysosomal Storage

Glucosylceramide, a degradation product of complex glycosphingolipids, is hydrolysed in lysosomes by glucocerebrosidase (GlcCerase). Mutations in the human GlcCerase gene cause a reduction in GlcCerase activity and accumulation of glucosylceramide, which results in the onset of Gaucher disease, the most common lysosomal storage disease. Significant clinical heterogeneity is observed in Gaucher disease, with three main types known, but no clear correlation has been reported between the different types and levels of residual GlcCerase activity. We now demonstrate that a correlation exists by using a radioactive, short-acyl chain substrate, N-(1-[14C]hexanoyl)-D-erythro-glucosylsphingosine ([14C]hexanoyl-GlcCer). This substrate rapidly transferred into biological membranes in the absence of detergent [Futerman and Pagano (1991) Biochem. J. 280, 295-302] and was hydrolyzed to N-(1-[14C]hexanoyl)-D-erythro-sphingosine ([14C]hexanoyl-Cer) both in vitro and in situ, with an acid pH optimum. A strict correlation was observed between levels of [14C]hexanoyl-GlcCer hydrolysis and Gaucher type in human skin fibroblasts. The mean residual activity measured in vitro for 3 h incubation in type 1 Gaucher fibroblasts (the mild form of the disease) was 46.3 +/- 4.6 nmol of [14C]hexanoyl-Cer formed per mg protein (n = 9), and in type 2 and 3 fibroblasts (the neuronopathic forms of the disease) was 19.6 +/- 6.5 (n = 9). A similar correlation was observed when activity was measured in situ, suggesting that the clinical severity of a lysosomal storage disease is related to levels of residual enzyme activity.

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Engraftment of human CD34+ cells leads to widespread distribution of donor-derived cells and correction of tissue pathology in a novel murine xenotransplantation model of lysosomal storage disease

Blood ◽

10.1182/blood-2002-08-2597 ◽

2003 ◽

Vol 101 (5) ◽

pp. 2054-2063 ◽

Cited By ~ 33

Author(s):

A. Alex Hofling ◽

Carole Vogler ◽

Michael H. Creer ◽

Mark S. Sands

Keyword(s):

Bone Marrow ◽

Lysosomal Storage Disease ◽

Storage Disease ◽

Human Cells ◽

Therapeutic Effects ◽

Lysosomal Storage ◽

Human Cd34 ◽

Quantitative Measurements ◽

Characteristic Features

A novel murine system was developed to study the in vivo localization of xenotransplanted human cells and assess their therapeutic effect in an authentic model of disease. The β-glucuronidase (GUSB) mutation of the mucopolysaccharidosis type VII (MPSVII) mouse was backcrossed onto the nonobese diabetic/severe combined immunodeficient (NOD/SCID) xenotransplantation strain. The resulting NOD/SCID/MPSVII mice displayed the characteristic features of lysosomal storage disease because of GUSB deficiency and were also capable of engrafting human cells. Human CD34+hematopoietic progenitor cells from healthy, GUSB+donors engrafted NOD/SCID/MPSVII mice in a manner similar to that of standard NOD/SCID mice. Six to 12 weeks following transplantation, 1% to 86% of the host bone marrow was positive for human CD45. By using a GUSB-specific histochemical assay, human engraftment was detected with single-cell sensitivity not only in well-characterized hematopoietic tissues like bone marrow, spleen, lymph node, and thymus, but also in other nonhematopoietic organs like liver, kidney, lung, heart, brain, and eye. Quantitative measurements of GUSB activity confirmed this expansive tissue distribution. The GUSB-specific assays were validated for their accuracy in identifying human cells through colocalization of human CD45 expression with GUSB activity in tissues of mice receiving transplants. An analysis of the therapeutic effects of engrafted human cells revealed a reduction of pathologic storage material in host organs, including the bone, spleen, and liver. Such xenotransplantation experiments in the NOD/SCID/MPSVII mouse represent a powerful approach to both study the in vivo biology of human cells and gather preclinical data regarding treatment approaches for a human disease.

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Lipoid proteinosis of the larynx

The Journal of Laryngology & Otology ◽

10.1258/002221502760238082 ◽

2002 ◽

Vol 116 (9) ◽

pp. 736-739 ◽

Cited By ~ 10

Author(s):

Ferhan Öz ◽

Nuran Kalekoglu ◽

Baris Karakullukçu ◽

Özcan Öztürk ◽

Büge Öz

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Rare Disease ◽

Lysosomal Storage Disease ◽

Storage Disease ◽

Lysosomal Storage ◽

Upper Aerodigestive Tract ◽

Lipoid Proteinosis ◽

The Central Nervous System ◽

Chronic Laryngitis

Lipoid proteinosis is a rare disease that presents with hyaline deposits in many tissues. It involves predominantly the skin and upper aerodigestive tract, presenting with small yellowish papules and hoarseness. It may involve the central nervous system and cause intracerebral calcifications. Laryngeal lesions may resemble singer’s nodule or chronic laryngitis. The pathogenesis of the disease is not clear although several studies suggest a defective collagen production and/or lysosomal storage disease. In this article two cases with skin and larynx involvement are reported.

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Lipoid proteinosis: a lysosomal storage disease?

British Journal of Dermatology ◽

10.1111/j.1365-2133.1983.tb11560.x ◽

1983 ◽

Vol 109 (s24) ◽

pp. 19-20

Author(s):

J.I. Harper ◽

I. Barnes ◽

M.I. Filipe ◽

M. Dean ◽

R.C.D. Staughton ◽

...

Keyword(s):

Lysosomal Storage Disease ◽

Storage Disease ◽

Lysosomal Storage ◽

Lipoid Proteinosis

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Faculty Opinions recommendation of Oncogenic effects of germline variants in lysosomal storage disease genes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736262531.793563285 ◽

2019 ◽

Author(s):

Fowzan S Alkuraya

Keyword(s):

Lysosomal Storage Disease ◽

Storage Disease ◽

Disease Genes ◽

Lysosomal Storage ◽

Germline Variants

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Is there a role for scintigraphic imaging of bone manifestations in Gaucher disease?

Nuklearmedizin ◽

10.3413/nukmed-0142 ◽

2008 ◽

Vol 47 (06) ◽

pp. 239-247 ◽

Cited By ~ 8

Author(s):

S. Kohlfürst ◽

H. J. Gallowitsch ◽

E. Kresnik ◽

P. Lind ◽

A. B. Mehta ◽

...

Keyword(s):

Bone Marrow ◽

Lysosomal Storage Disease ◽

Gaucher Disease ◽

Storage Disease ◽

Lysosomal Storage ◽

Scintigraphic Imaging ◽

Imaging Methods ◽

X Ray ◽

Deficient Activity

SummaryGaucher disease is the most prevalent inherited, lysosomal storage disease and is caused by deficient activity of the enzyme β-glucocerebrosidase. Bone and bone marrow alterations are frequent in the most prevalent non-neuronopathic form of Gaucher disease. Imaging of bone manifestations in Gaucher disease is performed by a variety of imaging methods, conventional X-ray and MRI as the most frequently and most important ones. However, different modalities of scintigraphic imaging have also been used. This article gives an overview on scintigraphic imaging with respect to bone manifestations in Gaucher disease discussing the advantages and limitations of scintigraphic imaging in comparison to other imaging methods.

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