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Updated: May 12, 2026
In Vivo Modeling of the Morbid Human Genome using Danio rerio
Published on: August 24, 2013
Mouse models of fukutin-related protein mutations show a wide range of disease phenotypes
Anthony Blaeser1, Elizabeth Keramaris, Yiumo M Chan
1McColl-Lockwood Laboratory for Muscular Dystrophy Research, Neuromuscular/ALS Center, Carolinas Medical Center, Charlotte, NC 28231, USA. anthony.blaeser@carolinashealthcare.org
Abstract:
Dystroglycanopathies are characterized by a reduction in the glycosylation of alpha-dystroglycan (α-DG). A common cause for this subset of muscular dystrophies is mutations in the gene of fukutin-related protein (FKRP). FKRP mutations have been associated with a wide spectrum of clinical severity from severe Walker-Warburg syndrome and muscle-eye-brain disease with brain and eye defects to mild limb-girdle muscular dystrophy 2I with myopathy only. To examine the affects of FKRP mutations on the severity of the disease, we have generated homozygous and compound heterozygous mouse models with human mutations in the murine FKRP gene. P448Lneo+ and E310delneo+ mutations result in severe dystrophic and embryonic lethal phenotypes, respectively. P448Lneo+/E310delneo+ compound heterozygotes exhibit brain defects and severe muscular dystrophies with near absence of α-DG glycosylation. Removal of the Neo(r) cassette from the P448Lneo+ homozygous mice eliminates overt brain and eye defects, and reduces severity of dystrophic phenotypes. Furthermore, introduction of the common L276I mutation to generate transgenic L276Ineo+ homozygous and L276Ineo+/P448Lneo+ and L276Ineo+/E310delneo+ compound heterozygotes results in mice displaying milder dystrophies with reduced α-DG glycosylation and no apparent brain defects. Limited sampling and variation in functionally glycosylated α-DG levels between and within muscles may explain the difficulties in correlating FKRP expression levels with phenotype in clinics. The nature of individual mutations, expression levels and status of muscle differentiation all contribute to the phenotypic manifestation. These mutant FKRP mice are useful models for the study of disease mechanism(s) and experimental therapies.
Insights
FKRP mutations cause dystroglycanopathies, a spectrum of muscular dystrophies. Mouse models reveal how specific FKRP mutations influence disease severity, brain defects, and alpha-dystroglycan glycosylation, aiding research into these genetic muscle disorders.
Area of Science:
- Genetics
- Neuromuscular Disorders
- Molecular Biology
Background:
- Dystroglycanopathies are a group of inherited muscle diseases characterized by defective glycosylation of alpha-dystroglycan (α-DG).
- Mutations in the fukutin-related protein (FKRP) gene are a significant cause of dystroglycanopathies, leading to a wide range of clinical presentations, from severe brain and eye abnormalities to milder muscle weakness.
- Understanding the genotype-phenotype correlation in FKRP-related disorders is crucial for diagnosis and therapeutic development.
Purpose of the Study:
- To investigate the impact of specific FKRP mutations on disease severity and associated phenotypes.
- To generate and characterize FKRP mutant mouse models that mimic human dystroglycanopathies.
- To explore the relationship between FKRP mutations, α-DG glycosylation, and clinical manifestations.
Main Methods:
- Generation of homozygous and compound heterozygous FKRP mutant mouse models carrying human mutations.
- Phenotypic analysis of mutant mice, including assessment of brain and eye defects, muscular dystrophy, and α-DG glycosylation levels.
- Introduction of additional FKRP mutations (e.g., L276I) to study their combined effects.
Main Results:
- FKRP mutations P448Lneo+ and E310delneo+ resulted in severe muscular dystrophy and embryonic lethality, respectively.
- Compound heterozygotes (P448Lneo+/E310delneo+) exhibited brain defects and severe muscular dystrophy with near-absent α-DG glycosylation.
- Modifications to the FKRP mutations, such as Neo(r) cassette removal or introduction of the L276I mutation, modulated disease severity, reduced brain defects, and altered α-DG glycosylation levels.
Conclusions:
- FKRP mutant mouse models accurately recapitulate aspects of human dystroglycanopathies, including variable clinical severity and α-DG glycosylation defects.
- The specific nature of FKRP mutations, expression levels, and muscle differentiation status significantly influence phenotypic outcomes.
- These mouse models provide valuable tools for studying disease mechanisms and evaluating potential therapeutic strategies for FKRP-related dystroglycanopathies.
