{
  "abstract": "Background Desmin (DES) is a major intermediate filament protein involved in the structural integrity and function of striated muscles. Pathogenic mutations in DES are predominantly missense variants, causing isolated cardiomyopathy and combinations of myopathy and cardiomyopathy. In-frame insertions are very rare and usually classified as variants of uncertain significance or likely pathogenic due to limited predictive and/or experimental evidence.Methods This study describes a novel heterozygous in-frame insertion in exon 6 of DES (RefSeq NM_001927.4:c.1059_1061dup) identified in an Argentine family with myofibrillar myopathy (MFM). This mutation results in the duplication of a glutamic acid residue at position 353 (NP_001918.3:p.(Glu353dup)), in the 2B subdomain of the central rod domain. Clinical, computational and functional analyses were performed to study the pathogenicity of this variant.Results Clinically, the index patient exhibited hallmark MFM features, including progressive muscle weakness, atrophy and fatty muscle replacement. In silico analyses of molecular dynamics revealed that p.Glu353dup alters DES dimer assembly by stabilising an aberrant coiled-coil conformation, a mechanism not previously proposed for DES mutations. Functional studies in HEK293T cells and C2C12 myocytes suggested that the p.Glu353dup variant induces aberrant DES aggregation, confirming its detrimental effect on filament organisation.Conclusion These findings are consistent with the idea that p.Glu353dup is a pathogenic variant, supported by clinical studies, in silico protein modelling and functional evidence, highlighting the impact of in-frame insertions on DES filament homeostasis. By providing computational and experimental evidence, this study expands our understanding of desminopathies and offers new perspectives for pathogenicity assessment of uncertain DES variants.",
  "authors": [
    {
      "affiliations": [
        "Laboratorio de Investigación Aplicada a Neurociencias (LIAN), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Instituto de Neurociencias (INEU), CONICET, Belen de Escobar, Buenos Aires, Argentina"
      ],
      "name": "Sheila Lucia Castañeda"
    },
    {
      "affiliations": [
        "Laboratorio de Investigación Aplicada a Neurociencias (LIAN), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Instituto de Neurociencias (INEU), CONICET, Belen de Escobar, Buenos Aires, Argentina"
      ],
      "name": "Guadalupe Amin"
    },
    {
      "affiliations": [
        "Departamento de Química Biológica, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina"
      ],
      "name": "Maria Ines Freiberger"
    },
    {
      "affiliations": [
        "Laboratorio de Investigación Aplicada a Neurociencias (LIAN), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Instituto de Neurociencias (INEU), CONICET, Belen de Escobar, Buenos Aires, Argentina"
      ],
      "name": "Federico Zabalegui"
    },
    {
      "affiliations": [
        "Laboratorio de Investigación Aplicada a Neurociencias (LIAN), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Instituto de Neurociencias (INEU), CONICET, Belen de Escobar, Buenos Aires, Argentina"
      ],
      "name": "Sol Renes"
    },
    {
      "affiliations": [
        "Departamento de Neuropatología, FLENI, Buenos Aires, Argentina"
      ],
      "name": "Agata Fernandez"
    },
    {
      "affiliations": [
        "Laboratorio de Genética y Biología Molecular, IFEC-CONICET, Universidad Nacional de Cordoba, Córdoba, Argentina"
      ],
      "name": "Alberto Luis Rosa"
    },
    {
      "affiliations": [
        "Departamento de Diagnóstico por Imágenes, FLENI, Buenos Aires, Argentina"
      ],
      "name": "Claudia Cejas"
    },
    {
      "affiliations": [
        "Departamento de Neurología, FLENI, Buenos Aires, Buenos Aires, Argentina"
      ],
      "name": "Jose Manuel Pastor Rueda"
    },
    {
      "affiliations": [
        "Laboratorio de Investigación Aplicada a Neurociencias (LIAN), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Instituto de Neurociencias (INEU), CONICET, Belen de Escobar, Buenos Aires, Argentina"
      ],
      "name": "Ariel Waisman"
    },
    {
      "affiliations": [
        "Laboratorio de Fisiología de Proteínas, Departamento de Química Biológica, Universidad de Buenos Aires, Buenos Aires, Argentina"
      ],
      "name": "Diego Ferreiro"
    },
    {
      "affiliations": [
        "Laboratorio de Investigación Aplicada a Neurociencias (LIAN), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Instituto de Neurociencias (INEU), CONICET, Belen de Escobar, Buenos Aires, Argentina"
      ],
      "name": "Gustavo Sevlever"
    },
    {
      "affiliations": [
        "Laboratorio de Investigación Aplicada a Neurociencias (LIAN), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Instituto de Neurociencias (INEU), CONICET, Belen de Escobar, Buenos Aires, Argentina"
      ],
      "name": "Santiago Miriuka"
    },
    {
      "affiliations": [
        "Laboratorio de Investigación Aplicada a Neurociencias (LIAN), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Instituto de Neurociencias (INEU), CONICET, Belen de Escobar, Buenos Aires, Argentina"
      ],
      "name": "Lucia Natalia Moro"
    }
  ],
  "title": "Novel in-frame variant in DES (p.Glu353dup) causes myofibrillar myopathy: clinical, in silico and functional studies",
  "uid": "7d9e6f94-fded-572a-aae2-93ce144b3f28"
}