FHL1-related reducing-body myopathy and other genetic forms of myofibrillar myopathies: composition of pathological protein aggregates revealed by laser capture microdissection and subsequent proteomic analysis

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The spectrum of four and a half LIM domain gene- (FHL1) associated myopathies (FHL1opathies) encompasses at least two distinct myopathies, the reducing body myopathy (RBM) and the X-chromosomal myopathy with postural muscle atrophy (XMPMA). Both are progressive myopathies with pathognomonic intracytoplasmic inclusions (cytoplasmic and reducing bodies) in the skeletal muscle tissue. The severe form of RBM often leads to death in early childhood. The applicants were independently involved in the discovery of FHL1 mutations to be causative for both diseases1,18. Furthermore, using laser microdissection of the intracytoplasmic inclusions and aggregates followed by nanoflow LC-MS/MS coupled with proteomic analysis in RBM muscle tissue specimens, a new approach was set for the discovery of underlying gene mutations in rare myopathies with structural abnormalities of skeletal muscle. In addition to specific inclusions, the histopathology of FHL1opathies overlaps with the spectrum of myofibrillar myopathies, with evidence of granulofilamentous material and Z-line alterations. Therefore these myopathies have to be included in the group of myofibrillar myopathies.The aims of our project are: 1. to define the clinical, histopathological, and mutational spectrum of FHL1opathies and their consequences for the disease mechanisms; 2. to define proteomic spectra of pathological protein aggregates from genetically classified myofibrillar myopathies and transgenic animals involved in this consortium; 3. to define new causative genes in unclassified forms of MFM by laser capture microdissection (LCM) pathological protein aggregates followed by proteomic and subsequent genetic analysis.