Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy

Abstract

The striated muscle sarcomeres are highly organized structures composed of actin (thin) and myosin (thick) filaments that slide past each other during contraction. The integrity of sarcomeres is controlled by a set of structural proteins, among which are titin, a giant molecule that contains several immunoglobulin (Ig)-like domains and associates with thin and thick filaments, and [alpha]-actinin, an actin cross-linking protein. Mutations in several sarcomeric and sarcolemmal proteins have been shown to result in muscular dystrophy and cardiomyopathy. On the other hand, the disease genes underlying several disease forms remain to be identified. Here we describe a novel 57 kDa cytoskeletal protein, myotilin. Its N-terminal sequence is unique, but the C-terminal half contains two Ig-like domains homologous to titin. Myotilin is expressed in skeletal and cardiac muscle, it co-localizes with [alpha]-actinin in the sarcomeric I--bands and directly interacts with [alpha]-actinin. The human myotilin gene maps to chromosome 5q31 between markers AFM350yB1 and D5S500. The locus of a dominantly inherited limb-girdle muscular dystrophy (LGMD1A) resides in an overlapping narrow segment, and a new type of distal myopathy with vocal cord and pharyngeal weakness (VCPMD) has been mapped to the same locus. The muscle specificity and apparent role as a sarcomeric structural protein raise the possibility that defects in the myotilin gene may cause muscular dystrophy.

Caenorhabditis elegansKettin, a Large Immunoglobulin-like Repeat Protein, Binds to Filamentous Actin and Provides Mechanical Stability to the Contractile Apparatuses in Body Wall Muscle

“…However, kettin might be functionally homologous to palladin (Parast and Otey, 2000), myopalladin (Bang et al, 2001), and myotilin (Salmikangas et al, 1999), which have two to five Ig-repeats and localize to the Z-lines of vertebrate striated muscle. These proteins are critical for actin filament reorganization in nonmuscle cells (Boukhelifa et al, 2001(Boukhelifa et al, , 2003Salmikangas et al, 2003;Otey et al, 2005) and myofibril assembly in muscle cells (Bang et al, 2001;Salmikangas et al, 2003;Otey et al, 2005).…”

“…These proteins are critical for actin filament reorganization in nonmuscle cells (Boukhelifa et al, 2001(Boukhelifa et al, , 2003Salmikangas et al, 2003;Otey et al, 2005) and myofibril assembly in muscle cells (Bang et al, 2001;Salmikangas et al, 2003;Otey et al, 2005). In particular, myotilin directly binds to actin filaments, and its mutations in the human gene are associated with limb girdle muscular dystrophy 1A (Salmikangas et al, 1999) and myofibrillar myopathy (Selcen and Engel, 2004), which are termed myotilinopathies (Goebel, 2005;Olive et al, 2005). Therefore, C. elegans could be an excellent model to study functions of actin binding proteins with Ig-repeats in muscle and their interaction with other myofibrillar proteins.…”

The N-terminus of the long MLCK induces a disruption in normal spindle morphology and metaphase arrest

“…The Ig-C2 motif was originally identified in the extracellular domain of adhesion molecules (Williams and Barclay, 1988) but this motif is now recognized in a number of intracellular cytoskeletal proteins including titin, MyBP-C, MyBP-M, MyBP-H, myotilin and palladin (Einheber and Fischman, 1990;Labeit et al, 1990;Noguchi et al, 1992;Parast and Otey, 2000;Salmikangas et al, 1999;Vaughan et al, 1993). It is notable that most of these molecules are specific to skeletal muscle, suggesting that the C2 motifs contribute to the maintenance of cytoskeletal architecture and organization.…”

Telethonin and Other New Proteins of the Z‐Disc of Skeletal Muscle

“…However, the CaM domain in muscle is not able to bind calcium. As is described later, several Z-disc proteins have been reported to bind ®-actinin 2, including nebulin (14 ), ALP (15 ), FATZ (16 ), myotilin (17 ), titin (18)(19)(20), and ZASP (21).…”