P.5.13 Remarkable muscle pathology in DNAJB6 mutated LGMD1D

Abstract

Limb girdle muscular dystrophies are a large group of both dominantly and recessively inherited muscle diseases. Dominantly inherited LGMD1 diseases are usually milder and later onset forms than recessive LGMD2. We have followed six Finnish families with LGMD1D and reported clinical and MRI findings in these families. All families represent the same DNAJB6 mutation, causing a F93L change in the ubiquitously expressed co-chaperone DNAJB6. The molecular pathogenesis of LGMD1D is mediated by defective chaperonal function leading to impaired handling of misfolded proteins which normally, without the defect, would be degraded and re-cycled. We have analyzeded 14 muscle biopsies obtained from 13 patients in six families at very different time points after onset of muscle weakness symptoms. All biopsies were from lower limb muscles, either vastus lateralis or gastrocnemius medialis and processed for routine histology, histochemistry as well as extensive immunohistochemistry and semithin sections with subsequent electron microscopy. Uniform findings were myopathic/dystrophic changes in all patients. Restricted and easily overlooked myofibrillar pathology in routine histopathology included protein aggregates reactive for Z-disk proteins such as myotilin, desmin and alphaB-crystallin was a regular finding in the early stages of pathology. These formed Z-disk alterations, streaming and dispersion of Z-disk material on the ultrastructural level. Later in the disease process the pathology was dominated by rimmed vacuolar pathology. These were reactive for several markers of defect autophagy such as ubiquitin, TDP-43, p62 and SMI-31. Since DNAJB6 is known to interact with members of the chaperone assisted autophagy complex (CASA), including BAG3 – a known myofibrillar myopathy causing gene, the molecular muscle pathology is apparently mediated through impaired functions of CASA and eventually other protein complexes needed for the maintenance of sarcomeric and Z-disk structures.