Alternative Splicing of SORBS1 Affects Neuromuscular Junction Integrity in Myotonic Dystrophy Type 1

Area of Science:

• Molecular Biology
• Genetics
• Neuroscience

Background:

• Myotonic dystrophy type 1 (DM1) is a genetic disorder causing muscle weakness due to CTG repeat expansion.
• This expansion disrupts RNA splicing by sequestering MBNL proteins, leading to widespread splicing defects.
• SORBS1 exon 25 misregulation was previously observed in DM1 models, suggesting its involvement in disease pathology.

Purpose of the Study:

• To investigate the role of SORBS1 exon 25 splicing misregulation in DM1.
• To assess the functional consequences of SORBS1 exon 25 exclusion in various model systems.

Main Methods:

• Human skeletal muscle biopsies from DM1 patients and controls were analyzed for SORBS1 exon 25 inclusion.
• Functional consequences were studied in mice, zebrafish, and human-induced pluripotent stem cell (hiPSC)-derived skeletal muscle cells.
• Antisense oligonucleotide-mediated exon skipping was used to mimic SORBS1 exon 25 exclusion.

Main Results:

• SORBS1 exon 25 inclusion was significantly reduced in DM1 skeletal muscle biopsies and adult patient samples.
• Forced SORBS1 exon 25 exclusion in mice caused neuromuscular junction degeneration.
• Misregulation of SORBS1 exon 25 in zebrafish and hiPSC-derived muscle cells impaired locomotion and acetylcholine receptor clustering.

Conclusions:

• SORBS1 alternative splicing is an MBNL-regulated process vital for skeletal muscle development and neuromuscular junction integrity.
• Aberrant SORBS1 splicing in DM1 contributes to neuromuscular communication deficits.
• This finding deepens the understanding of mRNA splicing's role in neuromuscular disorders like DM1.