Update: Molecular Markers of FSHD

Posted by Friends of FSH Research on Nov 23, 2025

Report by Dr. Tapscott
See also Molecular Markers of FSHD

Several studies have defined the functional, MRI, and molecular measurements of disease progression in FSHD. This proposal seeks to address two important barriers to using this knowledge to rapidly advance therapeutic development. First, the development of an animal model that recapitulates the progression of FSHD in humans would greatly speed preclinical testing of therapeutic interventions. Mice have some utility as preclinical models, but evolutionary differences in DUX4 and the comparable mouse Dux limit the use of mice for studies of disease progression. In contrast to mice, human DUX4 and the comparable pig DUXC appear to have maintained similarity and the expression of human DUX4 in pigs cells has consequences very similar to expression in human cells. This proposal seeks to determine whether pigs will be a better model and will analyze gene expression and histology in two different models of FSHD based on the expression of DUX4 in pig muscle cells. With funding from this award, we have sequenced RNA derived from ~72 muscle biopsies obtained from pigs with a tamoxifen-inducible DUX4 at different time points following induction. We are preparing a manuscript with our collaborators in the Jones lab describing the functional, histological, and molecular consequences of DUX4 expression in pig muscles that we hope will guide future research using the pig as a large animal model for FSHD. The second goal of this proposal was to test whether cells of the immune system, T cells and B cells, are responding to FSHD muscle and circulating in the blood to other muscles of the body and possibly cause inflammation. With funding from this award, we have isolated cells from FSHD muscle biopsies and performed T and B cell receptor sequencing. These show multiple small clones in the muscle tissues rather than a single dominant clone. We also have screened plasma from control and FSHD subjects for auto-antibodies and identified a candidate protein that appears targeted by antibodies in plasma from multiple FSHD subjects. Future work will focus on validating these findings using additional detection methods and plasma samples, as well as investigating their possible relation to the resident FSHD muscle immune cells.