New mutations in the PPBG gene lead to loss of PPCA protein which affects the level of the β-galactosidase/neuraminidase complex and the EBP-receptor
Autor: | Anna Caciotti, Gina Ancora, T Bardelli, Enrico Zammarchi, Alessandra d'Azzo, Sabrina Malvagia, Amelia Morrone, Maria Alice Donati |
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Rok vydání: | 2004 |
Předmět: |
Endocrinology
Diabetes and Metabolism DNA Mutational Analysis Population Cathepsin A Neuraminidase Receptors Cell Surface Biology medicine.disease_cause Biochemistry NEU1 Endocrinology Tropoelastin Genetics medicine Lysosomal storage disease Humans Molecular Biology Mutation Polymorphism Genetic Immunochemistry Binding protein Infant Newborn Sequence Analysis DNA Fibroblasts beta-Galactosidase medicine.disease Molecular biology Fibronectins Lysosomal Storage Diseases Lysosomal lumen Italy GLB1 Galactosialidosis |
Zdroj: | Molecular Genetics and Metabolism. 82:48-55 |
ISSN: | 1096-7192 |
Popis: | We describe the clinical findings, and the molecular and biochemical studies in an Italian family with recurrent hydrops fetalis due to galactosialidosis (GS). GS is a rare lysosomal storage disorder caused by a deficiency of the protective protein/cathepsin A (PPCA). This protein forms a high-molecular-weight complex with the hydrolases beta-galactosidase (GLB1) and neuraminidase (NEU1). By virtue of this association these two enzymes are correctly compartmentalized in lysosomes and protected against rapid proteolytic degradation. Controversial data show that PPCA is also present in a second complex, including the Elastin Binding Protein (EBP) the EBP-receptor, which is involved in elastogenesis, and NEU1. We investigated the potential role of the PPCA in both complexes. Two new genetic lesions (c60delG and IVS2+1 G > T) that lead to a frameshift and a premature stop codon were detected in the PPCA cDNA and genomic DNA of the patient. The deleterious effect of such mutations was confirmed by the complete absence of the PPCA protein on Western blots. Thus, we examined the effect of the loss of PPCA on the two protein complexes in the patient's fibroblasts. Interestingly, a reduced amount of both GLB1 and EBP proteins was detected. These data confirm that PPCA is present in two functional complexes one with GLB1 and NEU1 in the lysosomal lumen and the other with EBP at the cell surface. The reduction in GLB1 and EBP confirms that PPCA is essential for their integrity. |
Databáze: | OpenAIRE |
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