Myopathies associated with mutations in FHL1 are rare X-linked dominant myofibrillar myopathies. By clinical examination, histopathology, Sanger sequencing, and laser microdissection combined with quantitative mass spectrometry, we were able to identify the causative gene mutation and protein aggregate composition in two brothers with a late-onset X-linked scapulo-axio-peroneal myopathy. The severely progressive course of the disease revealed a remarkable intrafamilial variability of the clinical presentation. Protein aggregation and reducing bodies were observed in the muscle biopsy. Using quantitative mass spectrometry we identified the FHL1 protein as the component showing highest increased abundance in the aggregates in both patients, however strikingly in a different absolute amount in both brothers. Furthermore, we identified the causative C224W mutation in the fourth LIM-domain of FHL1 in both. Thus, of note is the striking evidence of reducing bodies in the muscle biopsy in both adults, and our proteomic data confirm the underlying gene defect with an intrafamilial variability by the ratio of the total protein content in the aggregates. We suggest that our combined approach has a high potential as a new tool for identification of causative gene mutations and raises hints on possibly intrafamilial variability in protein aggregation disorders. As all clinical subtypes and mutations in each exon of the FHL1 gene are associated with myofibrillar alterations and reducing bodies, we would like to suggest terming the whole group as FHL1-associated myopathies.
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