{
  "abstract": "The Z-disk is a multi-protein complex, connecting the lateral ends of sarcomeres. This connection provides structural stability and alignment, as well as transmitting force during contraction. The Z-disk requires different proteins to enforce this connection, some of these proteins include actin cross-linkers such as alpha-actinin and filamin C. Although not exclusively expressed in cardiac tissue, genetic variants in these proteins have been linked to cardiomyopathies. In the literature, limited work has been done to confirm the pathogenicity of these variants, which are often classed as variants of unknown significance. This in turn hinders the process of genetic testing and prevents the development of specialised treatments.This study hypothesises the variants identified to cause disruption to the sarcomeric structure and function. By causing aggregation, they may lead to impaired cardiomyocyte functions, resulting clinically in contractile impairment, fibrosis, and arrythmia.A missense variant M82K in Filamin C (FLNC) was identified in two families with inherited cardiomyopathies. It is located in the actin binding domain (ABD) of the protein and predicted to affect actin binding. To investigate this variant, the FLNC ABD (wildtype and M82K) were expressed in and purified from bacteria and used for biochemical experiments. The M82K was also introduced in a full length filamin C construct for mammalian expression.Protein biochemistry experiments with the ABD fragment confirmed abnormal behaviour of the protein in the presence of M82K variant. The mutant recombinant protein also showed increased protein aggregation and decreased thermal stability. Mammalian expression has helped to provide insights into how stability and localisation of filamin C are affected by the M82K change.Collectively, our experiments suggest a pathogenic potential of the FLNC M82K variant. Future work using induced pluripotent stem cell derived cardiomyocytes will provide more detailed insights into disease mechanisms.",
  "authors": [
    {
      "affiliations": [
        "Department of Cardiovascular Sciences, University of Birmingham"
      ],
      "name": "Bethany Jones"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Sciences, University of Birmingham"
      ],
      "name": "Maya Noureddine"
    },
    {
      "affiliations": [
        "School of Cardiovascular and Metabolic Health, University of Glasgow"
      ],
      "name": "Rachel Myles"
    },
    {
      "affiliations": [
        "School of Cardiovascular and Metabolic Health, University of Glasgow"
      ],
      "name": "Caroline Coats"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Sciences, University of Birmingham",
        "Division of Cardiovascular Medicine, University of Oxford"
      ],
      "name": "Katja Gehmlich"
    }
  ],
  "title": "1-026 Evaluating the pathogenic potential of a variant of unknown significance in filamin C",
  "uid": "f759dccd-b7d8-5e3c-a1df-6e961950fb30"
}