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Abnormalities in alpha-dystroglycan expression in MDC1C and LGMD2I muscular dystrophies
Susan C Brown1, Silvia Torelli, Martin Brockington
1Dubowitz Neuromuscular Unit, Department of Paediatrics, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, United Kingdom. s.brown@ic.ac.uk
Abstract:
We recently identified mutations in the fukutin related protein (FKRP) gene in patients with congenital muscular dystrophy type 1C (MDC1C) and limb girdle muscular dystrophy type 2I (LGMD2I). The sarcolemma of these patients typically displays an immunocytochemical reduction of alpha-dystroglycan. In this report we extend these observations and report a clear correlation between the residual expression of alpha-dystroglycan and the phenotype. Three broad categories were identified. Patients at the severe end of the clinical spectrum (MDC1C) were compound heterozygote between a null allele and a missense mutation or carried two missense mutations and displayed a profound depletion of alpha-dystroglycan. Patients with LGMD with a Duchenne-like severity typically had a moderate reduction in alpha-dystroglycan and were compound heterozygotes between a common C826A (Leu276Ileu) FKRP mutation and either a missense or a nonsense mutation. Individuals with the milder form of LGMD2I were almost invariably homozygous for the Leu276Ile FKRP mutation and showed a variable but subtle alteration in alpha-dystroglycan immunolabeling. Our data therefore suggest a correlation between a reduction in alpha-dystroglycan, the mutation and the clinical phenotype in MDC1C and LGMD2I which supports the hypothesis that dystroglycan plays a central role in the pathogenesis of these disorders.
Insights
Mutations in the fukutin related protein (FKRP) gene are linked to congenital muscular dystrophy type 1C (MDC1C) and limb girdle muscular dystrophy type 2I (LGMD2I). Reduced alpha-dystroglycan expression correlates with disease severity in these muscular dystrophy subtypes.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Mutations in the fukutin related protein (FKRP) gene cause congenital muscular dystrophy type 1C (MDC1C) and limb girdle muscular dystrophy type 2I (LGMD2I).
- Patients with these disorders often exhibit reduced alpha-dystroglycan expression on their sarcolemma.
Purpose of the Study:
- To investigate the correlation between residual alpha-dystroglycan expression and clinical phenotype in FKRP-related muscular dystrophies.
- To further elucidate the role of dystroglycan in the pathogenesis of MDC1C and LGMD2I.
Main Methods:
- Immunocytochemical analysis of alpha-dystroglycan expression.
- Genotyping of FKRP mutations in patients with MDC1C and LGMD2I.
- Correlation of genotype with clinical severity and alpha-dystroglycan levels.
Main Results:
- Three distinct categories of alpha-dystroglycan reduction were identified, correlating with clinical phenotypes.
- Severe MDC1C cases showed profound alpha-dystroglycan depletion.
- Moderate reduction was observed in Duchenne-like LGMD, often associated with a common FKRP mutation (C826A) and other mutations.
- Milder LGMD2I cases, frequently homozygous for the Leu276Ile FKRP mutation, displayed subtle alpha-dystroglycan alterations.
Conclusions:
- A clear correlation exists between FKRP genotype, alpha-dystroglycan expression levels, and the clinical phenotype in MDC1C and LGMD2I.
- These findings support the central role of dystroglycan in the pathogenesis of these muscular dystrophies.
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