Protective Protein/Cathepsin A Loss in Cultured Cells Derived from an Early-Infantile Form of Galactosialidosis Patients Homozygous for the A1184-G Transition (Y395C Mutation)

Itoh, Kohji; Shimmoto, Michie; Utsumi, Kouichi; Mizoguchi, Nobuyuki; Miharu, Norio; Ohama, Koso; Sakuraba, Hitoshi

doi:10.1006/bbrc.1998.8659

Cited by 6 publications

(1 citation statement)

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“…There have been only a few descriptions of the early-infantile form; however, recent case reports of an Italian patient with a mutant allelic combination of Val104Met/Leu208Pro described clinical and pathological abnormalities of the infantile form in detail [103,105]. A different mutation causing the early-infantile phenotype has also been identified in a Japanese family [109]. The patients were homozygotes for the Tyr367Cys substitution.…”

Section: Mutations In the Early-infantile Formmentioning

confidence: 99%

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: Mutations In the Early-infantile Formmentioning

confidence: 99%