Abstract
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.
Highlights
Myopathies are diseases of the skeletal muscle, which are frequently hereditary
Using exome sequencing in two probands, the variant ACTN2 p.Ala119Thr was ranked the most highly expressed in cardiac tissue according to data derived from RNAseq and found to cosegregate with disease of the four affected family members
Knock-in mice carrying either a heterozygous or homozygous form of MYPN p.Gln526X, homologous to the human MYPN p.Gln529X variant, reflected aspects of RCM when investigated by echocardiography, cardiac magnetic from the patients showed a complete absence of myopalladin in these individuals and supports the variants being loss-of-function
Summary
Myopathies (myo—muscle, pathy—suffering) are diseases of the skeletal muscle, which are frequently hereditary. There is phenotypic overlap between these diseases, e.g., ACM can affect primarily the left ventricle, mimicking DCM with arrhythmias [5] Likewise, both RCM and HCM are characterised by diastolic dysfunction [6]. We have selected Z-disc proteins that are implicated in genetic disease of both skeletal muscle and the heart, or cause myopathy with cardiac involvement. Using exome sequencing in two probands, the variant ACTN2 p.Ala119Thr was ranked the most highly expressed in cardiac tissue according to data derived from RNAseq and found to cosegregate with disease of the four affected family members. The missense variants in ACTN2 co-segregated with the disease in affected family members They showed adult-onset asymmetric distal muscle weakness, e.g., atrophy of the Tibialis anterior muscle, which later progressed to proximal limb muscles. A double knockout mouse model, lacking both dystrophin and α-actinin 3, showed reduced muscular strength but was protected from stretch-induced damage with age by an increase in oxidative muscle metabolism
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
