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Assignment of the human gene for the sarcomeric M-band protein myomesin (MYOM1) to 18p11.31-p11.32
(1998)
Chromosomal assignment of the human gene for endosarcomeric cytoskeletal M-protein (MYOM2) to 8p23.3
(1999)
Myofibrillar myopathy (MFM) is a human disease that is characterized by focal myofibrillar destruction and pathological cytoplasmic protein aggregations. In an extended German pedigree with a novel form of MFM characterized by clinical features of a limb-girdle myopathy and morphological features of MFM, we identified a cosegregating, heterozygous nonsense mutation (8130G -> A; W2710X) in the filamin c gene ( FLNC) on chromosome 7q32.1. The mutation is the first found in FLNC and is localized in the dimerization domain of filamin c. Functional studies showed that, in the truncated mutant protein, this domain has a disturbed secondary structure that leads to the inability to dimerize properly. As a consequence of this malfunction, the muscle fibers of our patients display massive cytoplasmic aggregates containing filamin c and several Z-disk-associated and sarcolemmal proteins
The KY protein has been implicated in a neuromuscular dystrophy in the mouse, but its role in muscle function remains unclear. Here, we show that KY interacts with several sarcomeric cytoskeletal proteins including, amongst others, filamin C and the slow isoform of the myosin-binding protein C. These interactions were confirmed in vitro and because of its central role in skeletal muscle disease, characterized in more detail for filamin C. A role for KY in regulating filamin C function in vivo is supported by the expression analysis of filamin C in the null ky mouse mutant, where distinct irregular subcellular localization of filamin C was found in subsets of muscle fibres, which appears to be a specific outcome of KY deficiency. Furthermore, KY shows protease activity in in vitro assays, and specific degradation of filamin C by KY is shown in transfected cells. Given the enzymatic nature of the KY protein, it is likely that some of the identified partners are catalytic substrates. These results suggest that KY is an intrinsic part of the protein networks underlying the molecular mechanism of several limb-girdle muscular dystrophies, particularly those where interactions between filamin C and disease causing proteins have been shown