Protective protein gene mutations in galactosialidosis.

Shimmoto, Michie; Fukuhara, Y; Itoh, Kohji; Oshima, Akihiro; Sakuraba, Hitoshi; Suzuki, Yoshiyuki

doi:10.1172/jci116472

Cited by 69 publications

(80 citation statements)

References 15 publications

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“…For transient expression of the wildtype and mutant lysosomal neuraminidase cDNAs, a fibroblast cell line derived from a galactosialidosis patient (ASVGS-1) (Shimmoto et al 1993;Gluzman et al 1981) or COS-1 cells (kindly supplied by Dr. Y. Nabeshima, National Institute of Neuroscience, NCNP, Tokyo, Japan) were cultured in the same medium.…”

Section: Cell Culturementioning

confidence: 99%

“…Briefly, a mixture comprising the plasmid DNA (5 µg) and DMRIE-C reagent (10 µl) was added to cells cultured in FCS-free Ham's F-10 medium, followed by incubation for 5 h. Then, the culture medium was replaced with Ham's F-10 medium containing 10% FCS, and the cells were cultured for 4 days. As for ASVGS-1 cells for enzyme assay and COS-1 cells for immunocytochemical analysis, a pCAGGS vector (Miyazaki et al 1991) containing human wild-type PPCA cDNA (pCAGGS-PP, 5 µg) (Shimmoto et al 1993) was cotransfected with the wild-type or mutant lysosomal neuraminidase cDNA.…”

Section: Gene Analysismentioning

confidence: 99%

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Molecular and structural studies of Japanese patients with sialidosis type 1

et al. 2000

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To gain insight into the pathogenesis of sialidosis type 1, we performed molecular investigations of two unrelated Japanese patients. Both of them are compound heterozygotes for base substitutions of 649 G-to-A and 727 G-to-A, which result in amino acid alterations V217M and G243R, respectively. Using homology modeling, the structure of human lysosomal neuraminidase was constructed and the structural changes caused by these missense mutations were deduced. The predicted change due to V217M was smaller than that caused by G243R, the latter resulting in a drastic, widespread alteration. The overexpressed gene products containing these mutations had the same molecular weight as that of the wild type, although the amounts of the products were moderately decreased. A biochemical study demonstrated that the expressed neuraminidase containing a V217M mutation was partly transported to lysosomes and showed residual enzyme activity, although a G243R mutant was retained in the endoplasmic reticulum/Golgi area and had completely lost the enzyme activity. Considering the data, we surmise that the V217M substitution may be closely associated with the phenotype of sialidosis type 1 with a late onset and moderate clinical course.

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Section: Cell Culturementioning

confidence: 99%

Section: Gene Analysismentioning

confidence: 99%

Molecular and structural studies of Japanese patients with sialidosis type 1

et al. 2000

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“…As to the late infantile form of galactosialidosis, only two kinds of missense mutations, reflecting mild phenotype (Y249N and F440V; the numbering is based on the initiation codon being taken as codon no. 1), have been reported so far (Shimmoto et al 1993;Zhou et al 1991Zhou et al , 1996.…”

Section: Introductionmentioning

confidence: 87%

“…Fibroblasts from a galactosialidosis patient with a decreased amount of PPCA mRNA were transformed with a simian virus 40-adenovirus recombinant, as previously described (Shimmoto et al 1993), and the transformed cell line, ASVGS-1, was used for expression and metabolic studies.…”

Section: Cell Culturementioning

confidence: 99%

“…The mutation results in a splicing defect and a decreased amount of PPCA mRNA. On the other hand, patients with the early infantile form of galactosialidosis are of panethnic origin, and a variety of missense mutations causing a deficiency of the mature PPCA have been reported (Shimmoto et al 1993;Zhou et al 1996). As to the late infantile form of galactosialidosis, only two kinds of missense mutations, reflecting mild phenotype (Y249N and F440V; the numbering is based on the initiation codon being taken as codon no.…”

Section: Introductionmentioning

confidence: 99%

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Structural and functional study of K453E mutant protective protein/cathepsin A causing the late infantile form of galactosialidosis

et al. 2000

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To clarify the molecular basis of the late infantile form of galactosialidosis, we characterized a defective protective protein/cathepsin A (PPCA) gene product with the K453E mutation newly found in an Arabic patient with this disease. Immunocytochemical, expression, and metabolic studies revealed that the precursor PPCA was synthesized but not processed to the mature form, and it was degraded in the mutant. A structural model of the mutant PPCA was constructed by amino acid substitution of 453 glutamic acid for lysine in the crystal structure of the wild type PPCA precursor reported. The results show that the K453E mutation is located at the dimer interface of the PPCA and reduces the hydrogen bond formation in the dimer. This structural change may cause instability of the PPCA dimer.

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Early-infantile galactosialidosis: Clinical, biochemical, and molecular observations in a new patient

et al. 1996

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Few patients with the early‐infantile form of galactosialidosis have been described to date. Presented here is the first Italian case. Fetal hydrops was detected by ultrasound at week 24 of gestation. At birth, the infant presented with hypotonia, massive edema, a flattened coarse facies, telangiectasias, and hepatosplenomegaly, but no dysostosis multiplex. The patient died 72 days postpartum. Excessive sialyloligosaccharides in urine, as well as vacuolation of lymphocytes and eosinophilic granulocytes in peripheral blood, were indicative of a lysosomal storage disease. In the patient's fibroblasts, both α‐neuraminidase and β‐galactosidase activities were severely reduced, and cathepsin A activity was <1% of control levels, confirming the biochemical diagnosis of galactosialidosis. However, in contrast to previously reported early‐infantile cases, a normal amount of protective protein/cathepsin A mRNA was detected on Northern blots. This mutant transcript was translated into a precursor protein that was not processed into the mature enzyme and lacked both protective and catalytic activities. © 1996 Wiley‐Liss, Inc.

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Protective protein gene mutations in galactosialidosis.

Abstract: Four different protective protein

Cited by 69 publications

References 15 publications

Molecular and structural studies of Japanese patients with sialidosis type 1

Molecular and structural studies of Japanese patients with sialidosis type 1

Structural and functional study of K453E mutant protective protein/cathepsin A causing the late infantile form of galactosialidosis

Early-infantile galactosialidosis: Clinical, biochemical, and molecular observations in a new patient

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