Molecular pathology of NEU1 gene in sialidosis

Abstract

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,

In vivo crystallography at X-ray free-electron lasers: the next generation of structural biology?

“…Cockroach milk protein (C.m.p.) is a cockroach protein involved in food storage [11]; hNeu1 is a human neuraminidase [12]. Type 1 and 2 refer to the viscosity of the extracted sample solution before injection, with type 1 samples being less viscous than type 2.…”

“…For every protein sample studied, the size of the crystals was sufficient for microscopic visualization. A typical crystal of a human neuraminidase [12] grown in vivo is shown in figure 2. Various methods were applied for identification and characterization of the crystals, including immunoblotting (figure 2), X-ray diffraction studies and rigorous extraction and analysis of the crystal content.…”

The Elastin Receptor Complex Transduces Signals through the Catalytic Activity of Its Neu-1 Subunit

“…Neu-1 catalyzes the removal of terminal sialic acid residues from oligosaccharides, glycoproteins, and glycolipids (31,32). The consequence is the release of sialic acid in the cellular environment.…”

“…Neu-1 is a member of the sialidase family and catalyzes the hydrolysis of terminal sialic acid residues of oligosaccharides, glycoproteins, and glycolipids (31,32). Importantly, it has been shown in vitro that the removal of ␤-Gal or PPCA hinders the formation of active neuraminidase, indicating that all three components of the complex are required for neuraminidase activity (33).…”

Sialidosis Presenting as Severe Nonimmune Fetal Hydrops is Associated with Two Novel Mutations in Lysosomal α-Neuraminidase

“…Of the NEU1 mutations identified to date, fewer than one-fourth have been associated with hydrops fetalis. 6 We report a case of sialidosis presenting as fetal hydrops in which two novel mutations in NEU1 were identified.…”