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Functional characterization of wild-type and mutant human sialin
Pierre Morin1, Corinne Sagné, Bruno Gasnier
1CNRS UPR 1929, Institut de Biologie Physico-Chimique, Paris, France.
The EMBO Journal
|October 29, 2004
Summary
Defective sialin transport causes infantile sialic acid storage disease (ISSD) and Salla disease. A new assay shows ISSD mutations halt transport, while Salla disease mutations slow it, explaining disease severity and neurological impacts.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- Sialic acid modification is crucial for biological processes.
- Defects in sialic acid metabolism lead to diseases like ISSD and Salla disease.
- Sialin, a lysosomal transporter, is implicated in these inherited disorders.
Purpose of the Study:
- To develop a functional assay for human sialin.
- To investigate the impact of pathogenic mutations on sialin transport.
- To understand the molecular basis of ISSD and Salla disease.
Main Methods:
- Redirecting human sialin to the plasma membrane via protein mutation.
- Developing a functional assay to measure neuraminic acid accumulation.
- Analyzing transport kinetics of wild-type and mutant sialin.
Main Results:
- A plasmalemmal sialin construct successfully accumulated neuraminic acid.
- ISSD-associated mutations (missense, deletion) abolished sialin transport.
- The Salla disease mutation (R39C) significantly slowed, but did not abolish, transport.
- Sialin transport rate correlates with disease severity.
Conclusions:
- The developed assay effectively characterizes human sialin function.
- Differential transport defects explain the varying severity of ISSD and Salla disease.
- Sialin is suggested to be rate-limiting for nervous system processes, explaining neurological symptoms in Salla disease.