Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/ijms22063058
Keywords
alpha-actinin 2; filamin C; myopalladin; myotilin; telethonin; Z-disc alternatively spliced PDZ-motif (ZASP); myopathy; cardiomyopathy; missense variant; truncating variant
Funding
- British Heart Foundation (BHF) [FS/12/40/29712, PG/15/113/31944, PG/19/45/34419]
- Oxford BHF Centre of Research Excellence [RE/13/1/30181]
- Wellcome Trust [201543/B/16/Z]
- National Centre for Replacement, Refinement and Reduction of Animals in Research (NC3R) [NC/T001747/1]
- Medical Research Council [MR/V009540/1]
- British Heart Foundation [AA/18/2/34218]
- Wellcome Trust [201543/B/16/Z] Funding Source: Wellcome Trust
- MRC [MR/V009540/1] Funding Source: UKRI
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The Z-disc is crucial for maintaining the structure and signaling function of the sarcomere in muscle cells. Six key Z-disc proteins, associated with myopathies and cardiomyopathies, play a significant role in force transduction and intracellular signaling. Evaluating the pathogenic variants and minor allele frequency of these proteins in population cohorts can help in re-evaluating their pathogenicity.
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: alpha-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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