Disease relevance of MYOT

• Since defects in the myotilin gene were recently reported to cause a form of autosomal dominant limb-girdle muscular dystrophy, our findings provide a further contribution to the molecular understanding of this disease [1].
• Indications for a novel muscular dystrophy pathway. gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin [1].
• We studied the expression and subcellular distribution of myotilin in nemaline myopathy, central core disease, centronuclear myopathy, and myopathies with tubular aggregates [2].
• Western blot analysis did not indicate an increased myotilin expression in nemaline myopathy muscle [2].
• A prominent myotilin immunostaining of nemaline rods and core lesions was detected in all ten cases of nemaline myopathy and five cases of central core disease [2].

High impact information on MYOT

• A single titin immunoglobulin domain, m4, interacts with a myomesin fragment spanning domains My4-My6 [3].
• myotilin Mutation found in second pedigree with LGMD1A [4].
• Both T57I and S55F are located outside the alpha-actinin and gamma-filamin binding sites within myotilin [4].
• This mutation has not been found in 392 control chromosomes and is located in the unique N-terminal domain of myotilin, only two residues from the T57I mutation reported elsewhere [4].
• Myotilin is a muscle-specific Z-disc protein with putative roles in myofibril assembly and structural upkeep of the sarcomere [5].

Biological context of MYOT

• RESULTS: The authors detected four missense mutations in 6 of 57 patients with MFM in the serine-rich exon 2 of MYOT, where the two previously identified LGMD1A mutations are located [6].
• The expression of myotilin in muscle cells is tightly regulated to the later stages of in vitro myofibrillogenesis, when preassembled myofibrils begin to align [7].
• Several myotilin point mutations have been described in patients with limb-girdle muscular dystrophy type 1A (LGMD1A), myofibrillar myopathy (MFM), spheroid body myopathy (SBM), three similar adult-onset, progressive and autosomal dominant muscular dystrophies [5].
• Functionally important regions in myotilin were identified by actin pull-down and yeast two-hybrid assays and with a novel strategy that combines in vitro DNA transposition-based peptide insertion mutagenesis with phenotype analysis in yeast cells [8].
• Therefore, TTID is unlikely to be the candidate tumor suppressor gene involved in malignant myeloid disorders [9].

Anatomical context of MYOT

• Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly [7].
• Here we show that myotilin also directly binds F-actin, efficiently cross-links actin filaments alone or in concert with alpha-actinin and prevents filament disassembly induced by Latrunculin A [7].
• The essential role of myotilin in skeletal muscle is attested by the observation that certain forms of myofibrillar myopathy and limb girdle muscular dystrophy are caused by mutations in the human myotilin gene [10].
• The Z-disc proteins myotilin and FATZ-1 interact with each other and are connected to the sarcolemma via muscle-specific filamins [10].
• 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 [11].

Associations of MYOT with chemical compounds

• We have identified a new myotilin mutation in an Argentinian pedigree with LGMD1 that is predicted to result in the conversion of serine 55 to phenylalanine (S55F) [4].
• Screening of the candidate gene titin immunoglobulin domain protein (TTID, also known as MYOT) detected a cytosine-to-thymine mutation in exon 2 of all clinically affected family members [12].
• Using sodium dodecyl sulphate-polyacrylamide gel electrophoresis, we demonstrated dose-dependent elevation of 57 kDa cytoskeletal-protein levels for arecoline [13].

Other interactions of MYOT

• On the one hand, filamin C is associated with the Z-disk of the myofibrillar apparatus and binds to myotilin; on the other hand, it interacts with the sarcoglycan complex at the sarcolemma [14].
• The palladin/myotilin/myopalladin family of actin-associated scaffolds [15].
• Expression of mutant myotilin leads to sarcomeric alterations in the dominantly inherited limb-girdle muscular dystrophy 1A and in myofibrillar myopathy/desmin-related myopathy [8].
• TTID: A novel gene at 5q31 encoding a protein with titin-like features [9].
• Evidence from immunoblotting assay indicated this 57 kDa cytoskeletal protein was vimentin [13].

Analytical, diagnostic and therapeutic context of MYOT

• On light microscopy, the nemaline structures were best identified in 3-mum-thick frozen sections stained trichromatically or immunostained for alpha-actinin or myotilin [16].

References