Molecular pathogenesis of hereditary inclusion body myopathies

Hereditary IBM constitutes a heterogeneous group of degenerative muscle disorders, inherited in recessive (IBM2/HIBM, OMIM 600737) or dominant traits (e.g. IBMPFD, OMIM 167320).

Mutations in GNE encoding UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) cause hereditary inclusion body myopathy (HIBM). To define the role of GNE mutations in HIBM pathogenesis, GNE protein expression was analyzed. GNE protein is expressed at equal levels in HIBM patients and normal control subjects. Immunofluorescence detection of GNE did not reveal any mislocalization of GNE in skeletal muscle. We conclude that impaired GNE function, not lack of expression, may be the key pathogenic factor in HIBM. For diagnostic purposes, direct genetic analysis of the GNE gene in patients diagnosed with IBM will remain the mainstay and is not aided by immunohistochemistry or immunoblotting using antibodies against the GNE protein.

Inclusion body myopathy with Paget disease and frontotemporal dementia is caused by mutations in valosin-containing protein (p97/VCP). The ubiquitin-selective chaperone p97/VCP is often required in protein degradation for substrate recruitment and ubiquitin chain assembly. In eukaryotes, p97/VCP is known to interact with UFD2a and CHIP homologues that regulate the myosin directed chaperone UNC-45 involved in functional muscle formation. Human UFD2a and CHIP partially colocalize with p97/VCP in the cytosol of wild-type and patient myoblasts, as well as in differentiated, multinucleated myotubes, and were excluded from the nucleus as visualized by immunofluorescence microscopy analysis. Remarkably, myotubes of IBMPFD patients did not display actin banding or the typically ordered alignment of the alpha-actinin positive myofibrillar array suggesting a severe defect in myofibril organization and sarcomere formation. In conclusion, we discovered an unanticipated function for p97/VCP in the process of myofibre differentiation, maintenance and regeneration, which is abolished in terminally differentiated myotubes derived from satellite cells of IBMPFD patients' muscle.