Functional and in silico assessment of MAX variants of unknown significance Articles uri icon


  • Comino Méndez, Iñaki
  • Leandro García, Luis J
  • Montoya, Guillermo
  • de Cubas, Aguirre A.
  • Currás Freixes, María
  • Tysoe, Carolyn
  • Izatt, Louise
  • Letón, Rocío
  • Gómez Graña, Álvaro

publication date

  • November 2015

start page

  • 1247

end page

  • 1255


  • 11


  • 93

International Standard Serial Number (ISSN)

  • 0946-2716


  • The presence of germline mutations affecting the MYCassociated protein X (MAX) gene has recently been identified as one of the now 11 major genetic predisposition factors for
    the development of hereditary pheochromocytoma and/or
    paraganglioma. Little is known regarding how missense variants
    of unknown significance (VUS) in MAX affect its pivotal
    role in the regulation of the MYC/MAX/MXD axis. In the
    present study, we propose a consensus computational prediction
    based on five Bstate-of-the-art^ algorithms. We also describe
    a PC12-based functional assay to assess the effects that
    12 MAX VUS may have on MYC's E-box transcriptional
    activation. For all but two of these 12 VUS, the functional
    assay and the consensus computational prediction gave consistent
    results; we classified seven variants as pathogenic and
    three as nonpathogenic. The introduction of wild-type MAX
    cDNA into PC12 cells significantly decreased MYC's ability
    to bind to canonical E-boxes, while pathogenic MAX proteins
    were not able to fully repress MYC activity. Further clinical
    and molecular evaluation of variant carriers corroborated the
    results obtained with our functional assessment. In the absence
    of clear heritability, clinical information, and molecular
    data, consensus computational predictions and functional
    models are able to correctly classify VUS affecting MAX