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Molecular and biochemical analysis of protective protein/cathepsin A mutations: correlation with clinical severity in
X Y Zhou1, A van der Spoel, R Rottier
1Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Insights
Genetic mutations in protective protein/cathepsin A (PPCA) cause galactosialidosis (GS). Specific PPCA mutations correlate with disease severity and presentation, aiding in understanding clinical heterogeneity in GS patients.
Area of Science:
- Genetics
- Biochemistry
- Lysosomal Storage Disorders
Background:
- Galactosialidosis (GS) is a lysosomal storage disorder caused by mutations in the protective protein/cathepsin A (PPCA) gene.
- GS presents with variable clinical severity, including early infantile (EI), late infantile (LI), and juvenile/adult (J/A) forms.
Purpose of the Study:
- To investigate the genotype-phenotype correlation in galactosialidosis by analyzing PPCA gene mutations in eight clinically diverse patients.
- To understand how specific PPCA mutations influence protein function, localization, and disease manifestation.
Main Methods:
- Analysis of PPCA gene mutations in eight GS patients with varying clinical presentations.
- Identification of novel point mutations and amino acid substitutions.
- Assessment of the impact of mutations on protein phosphorylation, lysosomal localization, and maturation.
Main Results:
- Four novel PPCA mutations (Val104Met, Leu208Pro, Gly411Ser, Ser23Tyr) were identified in EI and J/A patients, preventing proper protein processing.
- Two specific mutations (Phe412Val, Tyr221Asn) were found in LI patients and appear pathognomonic for this phenotype.
- Mutation allelic combinations influence clinical severity, with Phe412Val associated with more severe LI phenotypes than Tyr221Asn due to differences in intralysosomal stability.
Conclusions:
- Specific PPCA mutations are directly linked to the clinical heterogeneity observed in galactosialidosis.
- Understanding these genotype-phenotype correlations can aid in predicting disease progression and patient outcomes.
- This study provides insights into the molecular mechanisms underlying GS and highlights the importance of PPCA protein function.
Abstract:
Mutations in the gene encoding lysosomal protective protein/cathepsin A (PPCA) are the cause of the lysosomal disorder galactosialidosis (GS). Depending on age of onset and severity of the symptoms, patients present with either an early infantile (EI), a late infantile (LI), or a juvenile/adult (J/A) form of the disease. To study genotype-phenotype correlation in this disorder, we have analyzed the mutations in the PPCA gene of eight clinically different patients. In two EI and one J/A patient, we have identified four novel point mutations (Val104Met, Leu208Pro, Gly411Ser and Ser23Tyr), that prevent phosphorylation and, hence, lysosomal localization and maturation of the mutant precursors. Two amino acid substitutions (Phe412Val and Tyr221Asn) are shared by five LI patients. These mutations appear to be pathognomonic for this phenotype, and determine the clinical outcome depending on whether they are present together or in combination with other mutations. The latter include a single base deletion and a novel amino acid change (Met378Thr), which generates an additional glycosylation site. Within the LI group, patients carrying the Phe412Val mutation are clinically more severe than those with the Tyr221Asn substitution. This is in agreement with the biochemical behavior of the Asn221-mutant protein, that is, like the Phe412Val protein, phosphorylated, routed to lysosomes and proteolytically processed, but its intralysosomal stability is intermediate between that of wild-type PPCA and Val412-PPCA. Overall, these results may explain the clinical heterogeneity observed in GS patients and may help to correlate mutant allelic combinations with specific clinical phenotypes.