LEUTX mediates amplification of DUX4 signaling and aberrant myotube differentiation in facioscapulohumeral muscular dystrophy

LEUTX, but not ZSCAN4, is a major amplifier of DUX4 target gene expression in control and FSHD skeletal myocytes, enabling aberrant myotube differentiation.

• Why it matters: DUX4 target gene expression tracks FSHD severity, yet DUX4 itself is rare, leaving unclear how limited DUX4 activity becomes robust downstream activation and pathology.
• What they did: Functional analyses in control and FSHD skeletal myocytes tested LEUTX versus ZSCAN4, then used forced LEUTX expression to assess differentiation, mitotic gene persistence, DNA replication, and promoter access.
• The result: LEUTX disrupts muscle gene induction, promotes persistent mitotic gene expression, and causes aberrant DNA replication in myotube nuclei; it binds a subset of misregulated genes and requires DUX4 to activate DUX4 target promoters.