# DAB2 in LGMD R2: a molecular link between disease progression and lipid dysregulation

## TL;DR

Researchers found that DAB2 is a key indicator of disease progression and lipid issues in LGMD R2, a rare muscle disorder.

## Contribution

DAB2 is identified as a novel molecular and clinical marker linking dysferlin deficiency to lipid dysregulation and disease severity in LGMD R2.

## Key findings

- DAB2 levels increase with disease progression in LGMD R2 patient and mouse models.
- Restoring dysferlin via AAV reduces DAB2 levels, validating its role as a dynamic disease readout.
- High DAB2 expression correlates with lipid accumulation, and its knockdown reduces lipid buildup in LGMD R2 myotubes.

## Abstract

Limb-girdle muscular dystrophy R2 (LGMD R2) is an autosomal recessive disorder caused by dysferlin deficiency, leading to progressive muscle weakness and wasting. The lack of reliable clinical biomarkers has limited disease monitoring and therapeutic evaluation. Here, we identified Disabled-2 (DAB2) as a molecular and clinical indicator of disease state in LGMD R2. Transcriptomic profiling revealed a significant upregulation of DAB2 in induced pluripotent stem cell–derived (iPSC-derived) myotubes from patients, a finding validated in muscle biopsies from 14 dysferlin-deficient individuals and in dysferlin-deficient Bla/J mice, where DAB2 levels increased with disease progression. Importantly, AAV-mediated expression of full-length dysferlin restored DAB2 levels, supporting its value as a dynamic readout of disease activity for both disease monitoring and therapeutic response. Given the established role of DAB2 in clathrin-mediated endocytosis, particularly in LDL receptor internalization and cholesterol homeostasis, and the pathological lipid accumulation reported in LGMD R2, we investigated its contribution to lipid dysregulation. High DAB2 expression paralleled lipid deposition in patient muscles, iPSC-derived myotubes, and mouse tissue, whereas siRNA-mediated DAB2 knockdown reduced lipid accumulation in LGMD R2 myotubes. Collectively, these findings suggest that DAB2 functions as a mechanistic link between dysferlin deficiency, altered lipid handling, and disease severity, and they highlight its potential as a prognostic marker and therapeutic response measure for LGMD R2.

Researchers identify DAB2 as a promising marker linked to muscle damage and altered lipid handling in a rare muscle disease, LGMD R2.