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Mutational analysis in longest known survivor of mucopolysaccharidosis type VII
Stephan Storch1, Birgit Wittenstein, Rafiqul Islam
1UKE-University Hospital, Children's Hospital, University of Hamburg, Martinistrasse 52, Haus W23, 20246 Hamburg, Germany. storch@uke.uni-hamburg.de
Abstract:
Mucopolysaccharidosis VII (MPS VII) is an autosomal recessive disorder caused by the deficiency of beta-glucuronidase leading to the intralysosomal storage of heparan, dermatan, and chondroitin sulfate. Here, we report the identification of two novel missense mutations K350N and R577L in a 37-year-old patient with beta-glucuronidase deficiency and a relatively mild MPS VII phenotype. Expression of the K350N mutation in baby hamster kidney cells has revealed residual enzymatic activity and normal transport of the enzyme to the lysosome. However, expression of the R577L or the double mutant K350N/R577L results in rapid degradation of the enzyme in early biosynthetic compartments and a total loss of enzymatic activity. We attribute the mild phenotype to the residual catalytic activity provided by the K350N mutant. At the time of her death at the age of 37 years, this patient was the longest known survivor with MPS VII.
Insights
Mucopolysaccharidosis VII (MPS VII) is a rare genetic disorder. Novel mutations in beta-glucuronidase were identified in a patient with mild MPS VII, linking specific mutations to enzyme activity and survival.
Area of Science:
- Genetics
- Biochemistry
- Rare Diseases
Background:
- Mucopolysaccharidosis VII (MPS VII) is an autosomal recessive lysosomal storage disorder.
- It results from beta-glucuronidase deficiency, causing accumulation of glycosaminoglycans.
- MPS VII typically presents with severe clinical manifestations.
Observation:
- Two novel missense mutations, K350N and R577L, were identified in a 37-year-old MPS VII patient.
- The patient exhibited a relatively mild MPS VII phenotype.
- This patient represents the longest-known survivor with MPS VII.
Findings:
- The K350N mutation showed residual beta-glucuronidase enzymatic activity and normal lysosomal transport.
- The R577L mutation and the double K350N/R577L mutation led to enzyme degradation and loss of activity.
- The mild phenotype is attributed to the residual activity of the K350N mutant.
Implications:
- Understanding genotype-phenotype correlations in MPS VII is crucial for predicting disease severity.
- The K350N mutation offers insights into maintaining partial enzyme function in MPS VII.
- This study expands the knowledge of beta-glucuronidase mutations and their impact on MPS VII.
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