?-Galactosidase deficiency in juvenile and adult patients

Suzuki, Yuzuru; Nakamura, Norimasa; Fukuoka, Kazuko; Shimada, Yasuyuki; Uono, M

doi:10.1007/bf00273261

Cited by 95 publications

(18 citation statements)

References 23 publications

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“…The primary molecular defect in GM1 gangliosidosis and Morquio B syndrome is a deficiency of this enzyme. On the other hand, a hereditary disorder with i-galactosidase deficiency showing different clinical phenotypes from GM1 gangliosidosis was reported by Suzuki et al [71] and subsequently found to be a new lysosomal storage disease on the basis of clinical and biochemical analyses by Wenger et al [72]. The patients showed enzyme deficiency of neuraminidase as well as i-galactosidase, suggesting this genetic variant was different from other i-galactosidase deficiency diseases.…”

Section: Cathepsin a As An Essential Constituent Of The Lysosomal -Gamentioning

confidence: 93%

Cathepsin A/protective protein: an unusual lysosomal multifunctional protein

Hiraiwa¹

1999

Cellular and Molecular Life Sciences (CMLS)

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Cathepsin A/protective protein [3.4.16.5], carboxypeptidase A, is a lysosomal serine protease with structural homology to yeast (Saccharomyces cerevisiae) carboxypeptidase Y. Cathepsin A is a member of the alpha/beta hydrolase fold family and has been suggested to share a common ancestral relationship with other alpha/beta hydrolase fold enzymes, such as cholinesterases. Several lines of evidence indicate that cathepsin A is a multicatalytic enzyme with deamidase and esterase in addition to carboxypeptidase activities. Cathepsin A was recently identified in human platelets as deamidase. In vitro, it hydrolyzes a variety of bioactive peptide hormones including tachykinins, suggesting that extralysosomal cathepsin A plays a role in regulation of bioactive peptide functions. Recent reports emphasize the lysosomal protective function of cathepsin A rather than its protease function. The protective function of cathepsin A is distinct from its catalytic function. Human lysosomal beta-galactosidase and neuraminidase exist as a high molecular weight enzyme complex, in which there is a 54-kDa glycoprotein termed 'lysosomal protective protein'. Based on cell culture studies, protective protein was found to protect both beta-galactosidase and neuraminidase from intralysosomal proteolysis by forming a multienzyme complex and was shown to be deficient in patients with galactosialidosis, a combined deficiency of beta-galactosidase and neuraminidase. Molecular cloning and gene expression studies have disclosed that protective protein is cathepsin A. The cathepsin A precursor has the potential to restore both beta-galactosidase and neuraminidase activities in fibroblasts from patients with galactosialidosis. Cathepsin A knockout mice showed a phenotype similar to human galactosialidosis and the deficient phenotype found in the mutant mice was corrected by transplanting erythroid precursor cells overexpressing cathepsin A. Collectively, these findings demonstrate the significance of cathepsin A as a key molecule in the onset of galactosialidosis and also highlight the therapeutic potential of the cathepsin A precursor for patients with galactosialidosis.

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Section: Cathepsin a As An Essential Constituent Of The Lysosomal -Gamentioning

confidence: 93%

Cathepsin A/protective protein: an unusual lysosomal multifunctional protein

Hiraiwa¹

1999

Cellular and Molecular Life Sciences (CMLS)

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“…Age of onset is quite variable but usually is during the late infantile or juvenile period and survival is to adulthood. Clinically this type is character ized by pyramidal and extrapyramidal signs with gait disturbance and dystonic movements (table 1) [10][11][12][13][14][15]. Cases studied postmortem were limited to 3 but all showed similar unique distributional patterns of neu ronal storage affecting primarily basal ganglia [12,13].…”

Section: Gm] Gangliosidosismentioning

confidence: 99%

Neuropathology of Late Onset Gangliosidoses

Suzuki

1991

Dev Neurosci

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Neuropathological features of late onset gangliosidoses are reviewed. Although neuropathological studies are carried out on limited numbers of late onset cases, it appears that electron-dense heterogeneous conglomerates of neuronal inclusions increased with age admixed with more typical membranous cytoplasmic inclusions of gangliosidosis. Unlike early onset cases, which show extensive storage in cerebral cortical neurons, cortical neurons are involved less in late onset cases. In chronic (or adult) GM₁ gangliosidosis, neuronal storage is almost exclusively limited to the basal ganglia, while in chronic (or adult) GM₂ gangliosidosis storage neurons are more widely distributed in the thalamus, substantia nigra and other brainstem nuclei, and cerebellum is significantly affected.

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“…Since the observation by Okada and O'Brien (3) that the autosomal recessive disease Gm1-gangliosidosis is due to a /3-galactosidase deficiency, various patients with infantile, juvenile, and adult forms of this disease have been reported (4)(5)(6)(7). Analyses of interspecies hybrids indicated that the ,B-galactosidase deficiency in the various forms ofGM1-gangliosidosis is based on a mutation of a structural gene on chromosome 3 coding for the enzyme polypeptide (8).…”

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confidence: 99%

Molecular defect in combined beta-galactosidase and neuraminidase deficiency in man.

d’Azzo¹,

Hoogeveen²,

Reuser³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

336

193

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In normal human fibroblasts, an enzymically active 85,000-dalton precursor form of P-galactosidase is processed, via a number of intermediates, into a mature 64,000-dalton form. In addition there is an enzymically inactive 32,000-dalton component and its 54,000-dalton precursor. In fibroblasts from patients with a combined deficiency of P-galactosidase and neuraminidase these last two components are absent and hardly any mature /3-galactosidase can be demonstrated. Nevertheless, in the mutant fibroblasts, precursor f3-galactosidase is synthesized and processed normally. The excessive intralysosomal degradation that is responsible for the deficiency of mature P-galactosidase can be partially corrected by addition of the protease inhibitor leupeptin, which results in the accumulation of 85,000-dalton precursor P-galactosidase and of a partially processed 66,000-dalton form. When mutant cells were grown in the presence of a "corrective factor" purified from the medium of NH4CI-stimulated cell cultures, both (-galactosidase and neuraminidase activities were restored to low control levels. The immunoprecipitation pattern was completely normal after addition ofthe corrective factor, and mature 64,000-dalton (3-galactosidase accumulated in the mutant fibroblasts. We propose that the combined P-galactosidase/neuraminidase deficiency is caused by a defective 32,000-dalton glycoprotein which is normally required to protect /3-galactosidase and neuraminidase against excessive intralysosomal degradation and to give these enzymes their full hydrolytic activity.

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?-Galactosidase deficiency in juvenile and adult patients

Cited by 95 publications

References 23 publications

Cathepsin A/protective protein: an unusual lysosomal multifunctional protein

Cathepsin A/protective protein: an unusual lysosomal multifunctional protein

Neuropathology of Late Onset Gangliosidoses

Molecular defect in combined beta-galactosidase and neuraminidase deficiency in man.

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