Myofibrillar Myopathies and the Z-Disk Associated Proteins

Ruparelia, Avnika A.; Vaz, Raquel; Bryson-Richardson, Robert

doi:10.5772/50110

Cited by 5 publications

(14 citation statements)

References 249 publications

(307 reference statements)

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“…MYOT variants mainly manifest in myopathies such as LGMD, MFM, distal myopathy and spheroid-body myopathy [ 127 , 128 , 129 , 130 , 131 ] ( Table 4 ). Such diseases caused by pathogenic variants in MYOT are present in 10% of MFM patients and have been termed “myotilinopathies” [ 132 ].…”

Section: Z-disc Proteins In Myopathy and Cardiomyopathymentioning

confidence: 99%

The Role of Z-disc Proteins in Myopathy and Cardiomyopathy

Wadmore

Azad

Gehmlich

2021

IJMS

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The Z-disc acts as a protein-rich structure to tether thin filament in the contractile units, the sarcomeres, of striated muscle cells. Proteins found in the Z-disc are integral for maintaining the architecture of the sarcomere. They also enable it to function as a (bio-mechanical) signalling hub. Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle. This review will focus on six key Z-disc proteins: α-actinin 2, filamin C, myopalladin, myotilin, telethonin and Z-disc alternatively spliced PDZ-motif (ZASP), which have all been linked to myopathies and cardiomyopathies. We will summarise pathogenic variants identified in the six genes coding for these proteins and look at their involvement in myopathy and cardiomyopathy. Listing the Minor Allele Frequency (MAF) of these variants in the Genome Aggregation Database (GnomAD) version 3.1 will help to critically re-evaluate pathogenicity based on variant frequency in normal population cohorts.

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Section: Z-disc Proteins In Myopathy and Cardiomyopathymentioning

confidence: 99%

The Role of Z-disc Proteins in Myopathy and Cardiomyopathy

Wadmore

Azad

Gehmlich

2021

IJMS

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“…In the present study, we report a family carrying the first deletion disorders with clinical and genetic heterogeneity. 3,9 Causative mutations have been identified in genes encoding Z-disk or Z-diskassociated proteins and usually show an autosomal dominant inheritance. 3,9 MYOT mutations-related myopathies have been associated…”

Section: Discussionmentioning

confidence: 99%

“…3,9 Causative mutations have been identified in genes encoding Z-disk or Z-diskassociated proteins and usually show an autosomal dominant inheritance. 3,9 MYOT mutations-related myopathies have been associated…”

Section: Discussionmentioning

confidence: 99%

“…The myotilin gene (MYOT) encodes a 57-kDa sarcomeric Z-disk protein, which is expressed in skeletal muscle, cardiac muscle, and peripheral nerves. [1][2][3] Mutations in MYOT have been originally associated with different disorders subdivided according to the clinical and histological findings into three main categories including limb-girdle muscular dystrophy type 1A (LGMD1A), myofibrillar myopathy (MFM), and spheroid body myopathy. [1][2][3] Subsequently, LGMD1A has been classified as a form of MFM.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3] Mutations in MYOT have been originally associated with different disorders subdivided according to the clinical and histological findings into three main categories including limb-girdle muscular dystrophy type 1A (LGMD1A), myofibrillar myopathy (MFM), and spheroid body myopathy. [1][2][3] Subsequently, LGMD1A has been classified as a form of MFM. 4 These disorders are usually transmitted as an autosomal dominant trait, rarely a recessive pattern has been reported 5,6 and, to date, only missense mutations in MYOT have been described.…”

Section: Introductionmentioning

confidence: 99%

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A novel in‐frame deletion in MYOT causes an early adult onset distal myopathy

et al. 2023

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Missense mutations in MYOT encoding the sarcomeric Z‐disk protein myotilin cause three main myopathic phenotypes including proximal limb‐girdle muscular dystrophy, spheroid body myopathy, and late‐onset distal myopathy. We describe a family carrying a heterozygous MYOT deletion (Tyr4_His9del) that clinically was characterized by an early‐adult onset distal muscle weakness and pathologically by a myofibrillar myopathy (MFM). Molecular modeling of the full‐length myotilin protein revealed that the 4‐YERPKH‐9 amino acids are involved in local interactions within the N‐terminal portion of myotilin. Injection of in vitro synthetized mutated human MYOT RNA or of plasmid carrying its cDNA sequence in zebrafish embryos led to muscle defects characterized by sarcomeric disorganization of muscle fibers and widening of the I‐band, and severe motor impairments. We identify MYOT novel Tyr4_His9 deletion as the cause of an early‐onset MFM with a distal myopathy phenotype and provide data supporting the importance of the amino acid sequence for the structural role of myotilin in the sarcomeric organization of myofibers.

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Zebrafish models of BAG3 myofibrillar myopathy suggest a toxic gain of function leading to BAG3 insufficiency

et al. 2014

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Mutations in the co-chaperone Bcl2-associated athanogene 3 (BAG3) can cause myofibrillar myopathy (MFM), a childhood-onset progressive muscle disease, characterized by the formation of protein aggregates and myofibrillar disintegration. In contrast to other MFM-causing proteins, BAG3 has no direct structural role, but regulates autophagy and the degradation of misfolded proteins. To investigate the mechanism of disease in BAG3-related MFM, we expressed wild-type BAG3 or the dominant MFM-causing BAG3 (BAG3(P209L)) in zebrafish. Expression of the mutant protein results in the formation of aggregates that contain wild-type BAG3. Through the stimulation and inhibition of autophagy, we tested the prevailing hypothesis that impaired autophagic function is responsible for the formation of protein aggregates. Contrary to the existing theory, our studies reveal that inhibition of autophagy is not sufficient to induce protein aggregation. Expression of the mutant protein, however, did not induce myofibrillar disintegration and we therefore examined the effect of knocking down Bag3 function. Loss of Bag3 resulted in myofibrillar disintegration, but not in the formation of protein aggregates. Remarkably, BAG3(P209L) is able to rescue the myofibrillar disintegration phenotype, further demonstrating that its function is not impaired. Together, our knockdown and overexpression experiments identify a mechanism whereby BAG3(P209L) aggregates form, gradually reducing the pool of available BAG3, which eventually results in BAG3 insufficiency and myofibrillar disintegration. This mechanism is consistent with the childhood onset and progressive nature of MFM and suggests that reducing aggregation through enhanced degradation or inhibition of nucleation would be an effective therapy for this disease.

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Myofibrillar Myopathies and the Z-Disk Associated Proteins

Cited by 5 publications

References 249 publications

The Role of Z-disc Proteins in Myopathy and Cardiomyopathy

The Role of Z-disc Proteins in Myopathy and Cardiomyopathy

A novel in‐frame deletion in MYOT causes an early adult onset distal myopathy

Zebrafish models of BAG3 myofibrillar myopathy suggest a toxic gain of function leading to BAG3 insufficiency

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