The function of DUX4 in the thymus

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited myopathy
characterized by progressive and irreversible weakness, mostly starting in the
facial, shoulder, and upper arm muscles. FSHD is caused by misexpression of the
cleavage stage transcription factor DUX4 in skeletal muscles. DUX4 expression
is pathogenic for skeletal muscles, therefore several research groups are
focusing on reducing DUX4 expression as a therapeutic strategy for FSHD. DUX4
expression is currently considered to be limited to the luminal cells of the
testis and to cleavage stage embryos. However, a recent paper showed DUX4
expression in the thymus of a control individual, suggesting a function for
DUX4 in thymic cells. It is important to know the function of DUX4 outside the
germline since therapeutic strategies that block DUX4 may disturb this
function. We therefore propose to establish the function of DUX4 in the thymus.

The main goal of our study is to determine the function of DUX4 in the human
thymus by obtaining residual tissue from inevitable (incomplete) thymectomies
during open heart surgery in infants. Our primary objective is to detect
germline and skeletal muscle DUX4 transcripts in the thymus. Our secondary
objectives are to establish which cells in the thymus express DUX4 and to
determine which genes are silenced or activated upon DUX4 expression in the
thymus. Besides DUX4 expression, we will measure the expression of other thymic
genes that are related to FSHD but also to other skeletal muscle disorders.
Studying genes involved in skeletal muscle disorders will give us more
knowledge about the disease mechanisms involved in different skeletal muscle
disorders and will determine whether the thymus has a more general function in
skeletal muscle pathology.

This is an explorative, observational study on residual thymic tissue obtained
from standard care operative procedures in children < 3 years undergoing open
heart surgery for the first time. Thymic tissue will be collected
perioperatively and immediately processed. We expect to complete this study
within 3 years after start of inclusion.

As thymic tissue is removed during a first open heart surgery in infants < 3
years in a clinical care setting and is considered waste material, we do not
expect additional burden and/or risk for the study population. In conclusion,
we believe that the burden is minimal and in proportion to the potential value
of this study for other patients.