Diagnostically important muscle pathology in DNAJB6 mutated LGMD1D

Area of Science:

• Neurology
• Molecular Biology
• Genetics

Background:

• Limb girdle muscular dystrophies (LGMD) encompass inherited muscle disorders.
• LGMD1D arises from DNAJB6 mutations, impairing protein handling and degradation.
• Understanding LGMD1D muscle pathology is crucial for accurate diagnosis.

Purpose of the Study:

• To elucidate the muscle pathology in LGMD1D.
• To enhance diagnostic accuracy for LGMD1D patients.

Main Methods:

• Analysis of 21 muscle biopsies from 15 patients across six Finnish families.
• Utilized histochemistry, immunohistochemistry, and electron microscopy.
• Examined biopsies at various time points post-symptom onset.

Main Results:

• Observed myopathic/dystrophic changes with rimmed vacuoles and myofibrillar aggregates.
• Inclusions showed abnormal protein accumulation (myotilin, αB-crystallin, desmin) and Z-disk disorganization.
• Rimmed vacuoles indicated impaired autophagy (ubiquitin, TDP-43, p62, SMI-31 positive).

Conclusions:

• LGMD1D pathology involves impaired chaperone-assisted selective autophagy (CASA) and Z-disk maintenance.
• Dysfunctional CASA, potentially involving BAG3, contributes to myofibrillar myopathy.
• Histopathological findings provide diagnostic markers for LGMD1D.