The Role of Z-disc Proteins in Myopathy and Cardiomyopathy

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.

Keywords: Z-disc alternatively spliced PDZ-motif (ZASP); cardiomyopathy; filamin C; missense variant; myopalladin; myopathy; myotilin; telethonin; truncating variant; α-actinin 2.

Figure 1

Schematic representation of α-actinin shown as a dimer with variants in the ACTN2 gene that have been previously reported in individuals with myopathy (red) or cardiomyopathy (black). Solid lines represent missense variants. ABD—actin binding domain, EFh—EF hand, SR—spectrin like repeat. Created with BioRender.com (accessed on 7 March 22021). Adapted from [16].

Figure 2

Schematic representation of Filamin C shown as a dimer with missense variants in the FLNC gene that have been previously reported in individuals with myopathy (red) or cardiomyopathy (black). ABD—actin binding domain, Ig—immuno-globulin like domain. For truncating variants, please refer to Table 2. Created with BioRender.com (accessed on 7 March 2021).

Figure 3

Schematic representation of Myopalladin shown as a monomer with variants in the MYPN gene that have been previously reported in individuals with myopathy (red) or cardiomyopathy (black). Solid lines represent missense variants and dashed lines are truncations. Ig—immuno-globulin like domain, IS—interdomain insertion, Pro-rich—Proline-rich. Created with BioRender.com (accessed on 7 March 2021).

Figure 4

Schematic representation of Myotilin shown as a monomer with variants in the MYOT gene that have been previously reported in individuals with myopathy (red). Solid lines represent missense variants. Ig—immuno-globulin like domain, Ser-rich—Serine-rich, PBM—PDZ-binding motif. Created with BioRender.com (accessed on 7 March 2021).

Figure 5

Schematic representation of Telethonin shown as a monomer with variants in the TCAP gene that have been previously reported in individuals with myopathy (red) or cardiomyopathy (black). Solid lines represent missense variants and dashed lines are truncations. TB—titin binding domain. Created with BioRender.com (accessed on 7 March 2021).

Figure 6

Schematic representation of ZASP shown as a monomer with variants in the LDB3 gene that have been previously reported in individuals with myopathy (red) or cardiomyopathy (black). Solid lines represent missense variants. LIM—Lin-11 Isl-1 Mec-3 (LIM) domain, PDZ—PDZ domain, ZM—ZASP-like motif. Created with BioRender.com (accessed on 7 March 2021).