A mutation in myotilin causes spheroid body myopathy

Foroud, Tatiana; Pankratz, Nathan; Batchman, Amy P.; Pauciulo, Michael W.; Vidal, R.; Miravalle, Leticia; Goebel, Hans H.; Cushman, Lisa J.; Azzarelli, Biagio; Horak, Holli A.; Farlow, Martin R.; Nichols, William C.

doi:10.1212/01.wnl.0000188872.28149.9a

Cited by 79 publications

(39 citation statements)

References 15 publications

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“…Perhaps an even more challenging environment may be needed in order to reveal subtle changes in myo Ϫ/Ϫ mice. Myotilin mutations cause several forms of myotilinopathy, defined by clinical and morphological features as LGMD1A (13,12), myofibrillar myopathy (36,28), and spheroid body myopathy (7). To date, point mutations in the myotilin gene are clustered within exon 2 and result in single amino acid changes in a serine-rich amino-terminal region of myotilin.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, several novel disease entities caused by inherited mutations in Z-disk proteins have been identified. Among these are myotilinopathies, muscular disorders caused by missense mutations in the Z-disk protein myotilin (7,12,13,28,36). Myotilinopathies are characterized by proximal and/or distal muscle weakness, occasionally cardiomyopathy, elevated serum creatine kinase levels, and reduced tendon reflexes.…”

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confidence: 99%

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Targeted Deletion of the Muscular Dystrophy Gene myotilin Does Not Perturb Muscle Structure or Function in Mice

Moza

Mologni

Trokovic

et al. 2007

Molecular and Cellular Biology

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Myotilin, palladin, and myopalladin form a novel small subfamily of cytoskeletal proteins that contain immunoglobulin-like domains. Myotilin is a thin filament-associated protein localized at the Z-disk of skeletal and cardiac muscle cells. The direct binding to F-actin, efficient cross-linking of actin filaments, and prevention of induced disassembly of filaments are key roles of myotilin that are thought to be involved in structural maintenance and function of the sarcomere. Missense mutations in the myotilin-encoding gene cause dominant limb girdle muscular dystrophy type 1A and spheroid body myopathy and are the molecular defect that can cause myofibrillar myopathy. Here we describe the generation and analysis of mice that lack myotilin, myo ؊/؊ mice. Surprisingly, myo ؊/؊ mice maintain normal muscle sarcomeric and sarcolemmal integrity. Also, loss of myotilin does not cause alterations in the heart or other organs of newborn or adult myo ؊/؊ mice. The mice develop normally and have a normal life span, and their muscle capacity does not significantly differ from wild-type mice even after prolonged physical stress. The results suggest that either myotilin does not participate in muscle development and basal function maintenance or other proteins serve as structural and functional compensatory molecules when myotilin is absent.The muscle sarcomere is a strictly organized cytoskeletal structure responsible for force generation and transmission. The sarcomeric actin-containing thin filaments are aligned and anchored by the Z-disks, specialized three-dimensional structures composed of multiprotein complexes. In addition to thin filaments, Z-disks anchor laterally the sarcomere to the sarcolemma. Recently, several novel disease entities caused by inherited mutations in Z-disk proteins have been identified. Among these are myotilinopathies, muscular disorders caused by missense mutations in the Z-disk protein myotilin (7,12,13,28,36). Myotilinopathies are characterized by proximal and/or distal muscle weakness, occasionally cardiomyopathy, elevated serum creatine kinase levels, and reduced tendon reflexes. Typical morphological features include extensive disruption of the myofibrillar architecture, Z-disk streaming, and accumulation of apparently Z-diskassociated filamentous material. All known myotilinopathies are caused by missense mutations in the amino terminus of myotilin, and they are dominantly inherited and fully penetrant.Myotilin, together with palladin and myopalladin, forms a small subfamily of immunoglobulin (Ig)-like domain-containing cytoskeletal proteins (25). While the carboxy terminus of myotilin is highly conserved within the subfamily, its amino terminus is unique and rich in serine residues. Myotilin is mainly expressed in the skeletal and cardiac muscle (21,33), and it interacts with several structural Z-disk proteins, including ␣-actinin (33), actin (34, 41), filamin C (40), and FATZ-1 (calsarcin-2/myozenin-1) and FATZ-2 (calsarcin-1/myozenin-2) (10). The association with FATZ links myotilin ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Targeted Deletion of the Muscular Dystrophy Gene myotilin Does Not Perturb Muscle Structure or Function in Mice

Moza

Mologni

Trokovic

et al. 2007

Molecular and Cellular Biology

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“…For instance, myofibrillar myopathy (desmin-related myopathy), a disease characterized by sarcomere disintegration and accumulation of thin filament material, is caused by dominantly inherited missense mutations in Z-disc proteins: myotilin, filamin-C, and Z-band alternatively spliced PDZ motif-containing protein (ZASP, also named LIM domain-binding factor 3, Cypher, or Oracle) (42,43,52). Missense mutations in myotilin can also result in limbgirdle muscular dystrophy 1A and spheroid body myositis (10,18), while mutations in ZASP/Cypher (8,57), myopalladin or FATZ-2 (calsarcin-1/myozenin-2) have been found to be associated with dominant familial dilated (7,50) or hypertrophic cardiomyopathy (33). ZASP/Cypher knockout mice display a severe form of congenital myopathy and die postnatally (58), whereas myotilin knockout mice are virtually normal (31), suggesting redundancy between the myotilin family members and indicating that dysfunctional myotilin is more harmful to muscle cells than loss of the protein.…”

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confidence: 99%

A Class III PDZ Binding Motif in the Myotilin and FATZ Families Binds Enigma Family Proteins: a Common Link for Z-Disc Myopathies

Nandelstadh

Ismail

Gardin

et al. 2009

Molecular and Cellular Biology

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Interactions between Z-disc proteins regulate muscle functions and disruption of these interactions results in muscle disorders. Mutations in Z-disc components myotilin, ZASP/Cypher, and FATZ-2 (calsarcin-1/ myozenin-2) are associated with myopathies. We report here that the myotilin and the FATZ (calsarcin/ myozenin) families share high homology at their final C-terminal five amino acids. ThisL motif is present almost exclusively in these families and is evolutionary conserved. We show by in vitro and in vivo studies that proteins from the myotilin and FATZ (calsarcin/myozenin) families interact via this novel type of class III PDZ binding motif with the PDZ domains of ZASP/Cypher and other Enigma family members: ALP, CLP-36, and RIL. We show that the interactions can be modulated by phosphorylation. Calmodulin-dependent kinase II phosphorylates the C terminus of FATZ-3 (calsarcin-3/myozenin-3) and myotilin, whereas PKA phosphorylates that of FATZ-1 (calsarcin-2/myozenin-1) and FATZ-2 (calsarcin-1/ myozenin-1). This is the first report of a binding motif common to both the myotilin and the FATZ (calsarcin/ myozenin) families that is specific for interactions with Enigma family members.The sarcomere of striated muscle consists of strictly organized subunits, myosin-containing thick filaments and actincontaining thin filaments. The thin filaments are aligned and cross-linked at the Z-discs by a molecular complex in which ␣-actinin is one of the core structures. Since the contractile force is transduced via the Z-discs, this structure has special requirements. It must provide extensive stability and yet undergo modulation in response to external signals. The Z-discs also serve as important sensors of extracellular cues and mediators of cellular signals that result in various adaptive responses (37). Muscle cells are able to sense changes in their workload and adapt accordingly via complex signaling pathways, some involving calcium, since its level in muscle cells alters in response to nerve pulses and muscle contraction. Of special importance is calcineurin, a sarcomeric calcium/calmodulin-dependent phosphatase that can act as a sensor of change. It is involved in the regulation of genes affecting muscle differentiation and fiber-type specification (12, 13).The special role of the Z-discs is indicated by the fact that mutations in several Z-disc proteins can result in neuromuscular disorders and cardiomyopathies. For instance, myofibrillar myopathy (desmin-related myopathy), a disease characterized by sarcomere disintegration and accumulation of thin filament material, is caused by dominantly inherited missense mutations in Z-disc proteins: myotilin, filamin-C, and Z-band alternatively spliced PDZ motif-containing protein (ZASP, also named LIM domain-binding factor 3, Cypher, or Oracle) (42, 43, 52). Missense mutations in myotilin can also result in limbgirdle muscular dystrophy 1A and spheroid body myositis (10, 18), while mutations in ZASP/Cypher (8, 57), myopalladin or FATZ-2 (calsarcin-1/myozenin-2) have been ...

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“…Since this initial discovery, nine additional mutations in Myotilin (myofibrillar protein with Titin-like immunoglobulin domains) have been implicated in LGMD1A [10,[140][141][142], MFM [143], SBM [144] or late onset distal myopathy [145] with all mutations described to date displaying an autosomal dominant pattern of inheritance. One of the mutations identified, S55F, has been found as a cause of both LGMD [141] and MFM [143] suggesting there may be modifiers of the disease that determine the symptoms produced or that there is an overlap in the classification of these conditions that needs to be resolved.…”

Section: Myotilin and Myotilinopathiesmentioning

confidence: 99%

“…Pathology: spheroid bodies with Myotilin immunoreactivity at the periphery. Classified as spheroid body myopathy [144] c.164C>T…”

Section: Childhood60s Skelmentioning

confidence: 99%

Myofibrillar Myopathies and the Z-Disk Associated Proteins

Ruparelia¹,

Vaz²,

Bryson-Richardson³

2012

Skeletal Muscle - From Myogenesis to Clinical Relations

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A mutation in myotilin causes spheroid body myopathy

Abstract: A novel mutation in the TTID gene results in the clinical and pathologic phenotype termed "spheroid body myopathy." Mutations in this gene also cause limb-girdle muscular dystrophy 1A and are associated with myofibrillar myopathy.

Cited by 79 publications

References 15 publications

Targeted Deletion of the Muscular Dystrophy Gene myotilin Does Not Perturb Muscle Structure or Function in Mice

Targeted Deletion of the Muscular Dystrophy Gene myotilin Does Not Perturb Muscle Structure or Function in Mice

A Class III PDZ Binding Motif in the Myotilin and FATZ Families Binds Enigma Family Proteins: a Common Link for Z-Disc Myopathies

Myofibrillar Myopathies and the Z-Disk Associated Proteins

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