Sialidosis type I: first report in the Czech population of two siblings with cherry‐red spot myoclonus syndrome but without sialyloligosacchariduria

Ledvinová, Jana; Poupětová, Helena; Elleder, M; Tichý, J; Pěničková, V.; Harzer, K.

doi:10.1007/bf00735411

Cited by 4 publications

(3 citation statements)

References 3 publications

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“…That explains the reduction of the enzymatic activity to about 7% of the norm. A mild clinical phenotype of the patient homozygous for the T345I mutation correlated well with the observed high residual activity of the sialidase [Ledvinova et al, 1994].…”

Section: Missense Mutationssupporting

confidence: 64%

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Molecular pathology of NEU1 gene in sialidosis

Poupětová²,

et al. 2003

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Communicated by Mark H. PaalmanLysosomal sialidase (EC 3.2.1.18) has a dual physiological function; it participates in intralysosomal catabolism of sialylated glycoconjugates and is involved in cellular immune response. Mutations in the sialidase gene NEU1, located on chromosome 6p21.3, result in autosomal recessive disorder, sialidosis, which is characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. Sialidosis type I is a milder, late-onset, normosomatic form of the disorder. Type I patients develop visual defects, myoclonus syndrome, cherry-red macular spots, ataxia, hyperreflexia, and seizures. The severe early-onset form, sialidosis type II, is also associated with dysostosis multiplex, Hurler-like phenotype, mental retardation, and hepatosplenomegaly. We summarize information on the 34 unique mutations determined so far in the sialidase gene, including four novel missense and one novel nonsense mutations found in two Czech and two French sialidosis patients. The analysis of sialidase mutations in sialidosis revealed considerable molecular heterogeneity, reflecting the diversity of clinical phenotypes that make molecular diagnosis difficult. The majority of sialidosis patients have had missense mutations, many of which have been expressed; their effects on activity, stability, intracellular localization, and supramolecular organization of sialidase were studied. A structural model of sialidase allowed us to localize mutations in the sialidase molecule and to predict their impact on the tertiary structure and biochemical properties of the enzyme. Hum Mutat 22:343-352,

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Section: Missense Mutationssupporting

confidence: 64%

“…The Czech patient, with a previously described clinical case [Ledvinova et al, 1994], was homozygous for the c.1034C4T (p.T345I) substitution (Table 1). The T345I change is located in the beginning of the bW strand of the sialidase structure, in proximity to the active site residue R341 (Fig.…”

Section: Missense Mutationsmentioning

confidence: 99%

Molecular pathology of NEU1 gene in sialidosis

Poupětová²,

et al. 2003

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“…This mutation (c.1034C.T; p.T345I) changed the threonine (T) in the second Asn-X-Ser/Thr N-glycosylation site to an isoleucine (I) [24]. The patient was reported to have residual NEU1 enzymatic activity that correlated with an attenuated phenotype [25]. We hypothesized that, as is the case for the mut2-NEU1 variant, the omission of the second N-glycan on the NEU1 enzyme was at least partially responsible for the reduced NEU1 activity in the patients’ cells.…”

Section: Resultsmentioning

confidence: 99%

Protective protein/cathepsin A rescues N-glycosylation defects in neuraminidase-1

Wang

Zaitsev

Taylor

et al. 2009

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background-Neuraminidase-1 (NEU1) catabolizes the hydrolysis of sialic acids from sialoglycoconjugates. NEU1 depends on its interaction with the protective protein/cathepsin A (PPCA) for lysosomal compartmentalization and catalytic activation. Murine NEU1 contains 4 Nglycosylation sites, 3 of which are conserved in the human enzyme. The expression of NEU1 gives rise to differentially glycosylated proteins.Methods-We generated single-point mutations in mouse NEU1 at each of the 4 N-glycosylation sites. Mutant enzymes were expressed in NEU1-deficient cells in the presence and absence of PPCA.Results-All 4 N-glycosylation variants were targeted to the lysosomal/endosomal compartment. All N-glycans, with the exception of the most C-terminal glycan, were important for maintaining stability or catalytic activity. The loss of catalytic activity caused by the deletion of the second Nglycan was rescued by increasing PPCA expression. Similar results were obtained with a human NEU1 N-glycosylation mutant identified in a sialidosis patient.Conclusions-The N-terminal N-glycan of NEU1 is indispensable for its function, whereas the C-terminal N-glycan appears to be non-essential. The omission of the second N-glycan can be compensated for by upregulating the expression of PPCA.General Significance-These findings could be relevant for the design of target therapies for patients carrying specific NEU1 mutations.

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