[Current status and future prospects of research on Fukuyama muscular dystrophy]

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Fukuyama congenital muscular dystrophy (FCMD) is a common childhood muscular dystrophy in Japan.
• A specific SVA retrotransposal element insertion in the fukutin gene is found in all FCMD patients.
• This insertion leads to aberrant mRNA splicing, causing the disease.

Purpose of the Study:

• To elucidate the mechanism by which SVA insertion causes FCMD through aberrant mRNA splicing.
• To investigate the therapeutic potential of antisense oligonucleotides (AONs) for FCMD.
• To explore the role of fukutin and LARGE in ameliorating the muscular dystrophic phenotype.

Main Methods:

• Analyzing mRNA splicing in FCMD patient cells and model mice.
• Designing and introducing cocktail antisense oligonucleotides (AONs) targeting splice sites.
• Evaluating protein production, Fukutin function, and O-glycosylation of α-dystroglycan.
• Assessing the effects of myofiber-selective LARGE expression.

Main Results:

• Aberrant mRNA splicing induced by SVA exon-trapping was confirmed as the cause of FCMD.
• Three AONs effectively prevented pathogenic splicing in FCMD cells and model mice.
• AON treatment normalized Fukutin protein production and function, and O-glycosylation of α-dystroglycan.
• Fukutin was found to be essential for ameliorating the muscular dystrophic phenotype via LARGE expression.

Conclusions:

• Splicing modulation therapy using AONs shows promise as a radical clinical treatment for FCMD.
• Understanding the role of fukutin and LARGE provides further insights into FCMD pathogenesis and potential therapeutic strategies.