Fascioscapulohumeral Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited muscular dystrophy.  Patients show progressive weakness and atrophy of the muscles in the face, upper-arms and shoulder girdle to lower limbs, and a right/left asymmetrical involvement is common.  The disease is autosomal dominant and is associated with shortening of the D4Z4 repeat array from 11-100 to 1-10 copies in the 4q35 subtelomeric region.  The deletion is believed to have transcription derepression effect on genes near the D4Z4 locus, and several molecular mechanisms have been proposed to explain how the deletion might change transcription levels of genes in the vicinity.  By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, Dr. Chen’s group showed that paired-like homeodomain transcription factor 1 (PITX1) was specifically up-regulated in patients with FSHD.  In addition, we showed that the double homeobox 4 (DUX4) gene that maps within the D4Z4 repeat unit is a transcription activator of PITX1.  The results suggest that up-regulation of both DUX4 and PITX1 in FSHD muscles may play critical roles in the molecular mechanisms of the disease.  Our current research projects focus on 1) To identify additional transcriptionally regulated targets of DUX4 using genome-wide expression profiling and protein profiling.  The goal is to identify critical genes in additional to PITX1, which are involved in FSHD.  2) To identify molecular pathways involved in muscle atrophy induced by over-expressing Pitx1.  A tet-repressible muscle-specific Pitx1 transgenic mouse model has been generated and shown muscle atrophy phenotype after Pitx1 was induced.  The mouse model will also be used to study the molecular pathways involved and serves as a model for translational research.  3) To identify small molecules that can modify the expression of DUX4 and PITX1.  The goal is to identify potential therapeutic targets for treating FSHD.