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Molecular pathology of galactosialidosis in a patient affected with two new frameshift mutations in the cathepsin A/protective protein gene
Author(s) -
Richard Catherine,
Tranchemontagne Julie,
Elsliger MarcAndré,
Mitchell Grant A.,
Potier Michel,
Pshezhetsky Alexey V.
Publication year - 1998
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/(sici)1098-1004(1998)11:6<461::aid-humu7>3.0.co;2-f
Subject(s) - cathepsin a , biology , cathepsin h , cathepsin c , microbiology and biotechnology , cathepsin o , frameshift mutation , cathepsin l1 , cathepsin e , cathepsin d , cathepsin , mutation , gene , biochemistry , enzyme
Galactosialidosis is a recessively inherited lysosomal storage disease characterized by the combined deficiency of neuraminidase and β‐galactosidase secondary to the genetic deficiency of cathepsin A/protective protein. In lysosomes, cathepsin A forms a high‐molecular‐weight complex with β‐galactosidase and neuraminidase that protects these enzymes against intralysosomal proteolysis. In a patient affected with late infantile form of galactosialidosis, we found two new cathepsin A mutations, a two‐nucleotide deletion, c517delTT and an intronic mutation, IVS8+9C→G resulting in abnormal splicing and a five‐nucleotide insertion in the cathepsin A cDNA. Both mutations cause frameshifts and result in the synthesis of truncated cathepsin A proteins, which, as suggested by structural modeling, are incapable of dimerization, complex formation, and catalysis. However, enzymatic assays, gel‐filtration, and Western blot analysis of the patient's cultured skin fibroblast extracts showed the presence of a small amount of normal‐size, catalytically active cathepsin A and cathepsin A‐β‐galactosidase 680 kDa complex, suggesting that a low amount of cathepsin A mRNA is spliced normally and produces the wild‐type protein. This may contribute to the relatively mild phenotype of the patient and illustrates the importance of critically comparing molecular results with clinical and biochemical phenotypes. Hum Mutat 11:461–469, 1998. © 1998 Wiley‐Liss, Inc.