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Residual activity and proteasomal degradation of p.Ser298Pro sulfamidase identified in patients with a mild clinical phenotype of Sanfilippo A syndrome
Author(s) -
Muschol Nicole,
Pohl Sandra,
Meyer Ann,
Gal Andreas,
Ullrich Kurt,
Braulke Thomas
Publication year - 2011
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.34053
Subject(s) - missense mutation , mutant , endoplasmic reticulum , enzyme replacement therapy , phenotype , mutant protein , mutation , mucopolysaccharidosis , chemistry , microbiology and biotechnology , medicine , biology , endocrinology , gene , biochemistry , disease
Mucopolysaccharidosis type IIIA (MPS IIIA, Sanfilippo syndrome) is a fatal inherited lysosomal storage disease accompanied by progressive neurologic degeneration. The gene underlying MPS IIIA, SGSH , encodes a lysosomal enzyme, N ‐sulfoglucosamine sulfohydrolase (sulfamidase). Mutational analysis of a large cohort of MPS IIIA patients showed a correlation of the missense mutation p.Ser298Pro and a slowly progressive course of the disease. We report here on the expression of the mutant p.Ser298Pro sulfamidase in BHK cells retaining low residual activity. Pulse‐chase experiments showed that rapid degradation is responsible for the low steady state level of the mutant protein. Processing and secretion of p.Ser298Pro sulfamidase suggests that small amounts of the newly synthesized enzyme are transported to lysosomes. Most of the mutant sulfamidase exits the endoplasmic reticulum for proteasomal degradation. The ability to predict the clinical course of MPS IIIA in patients with the p.Ser298Pro mutation, as well as the residual enzymatic activity, and the reduced stability of the mutant sulfamidase suggest that this subgroup of patients is especially well suited to early sulfamidase replacement therapy or treatment with selective pharmacological chaperones. © 2011 Wiley‐Liss, Inc.