Facioscapulohumeral muscular dystrophy (FSHD) is a progressive skeletal muscle disorder that mainly affects the muscles of the face, shoulders and upper arms. Skeletal muscle wasting in FSHD is... Show moreFacioscapulohumeral muscular dystrophy (FSHD) is a progressive skeletal muscle disorder that mainly affects the muscles of the face, shoulders and upper arms. Skeletal muscle wasting in FSHD is caused by the failure to epigenetically repress the transcription factor DUX4 that is typically expressed during early development. DUX4 expression in skeletal muscle induces several myotoxic cascades that ultimately lead to the death of skeletal muscles cells. At the moment there is no molecular therapy that can delay or stop disease progression. The work described in this thesis mainly aims to gain more insight in the different FSHD mouse models and the in vivo testing of new therapies in FSHD mice. We describe the generation of one new mouse model and the characterization of two other FSHD mouse models. In addition, we tested a RNA therapy that blocks the DUX4 transcript in vivo. We show that this therapy could reduce DUX4 and DUX4 target genes in FSHD mice. In addition, the therapy alleviated the severity of skeletal muscle pathology. With the data described in this thesis we hope to accelerate the development and testing of new therapies for a disease that cannot be treated until this day. Show less
In this thesis two diseases that share a common feature of hypomethylation of repetitive DNA are studied: facioscapulohumeral muscular dystrophy (FSHD) and immunodeficiency, centromeric... Show moreIn this thesis two diseases that share a common feature of hypomethylation of repetitive DNA are studied: facioscapulohumeral muscular dystrophy (FSHD) and immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. In FSHD there is hypomethylation of the macrosatellite repeat D4Z4 and the associated DUX4 gene, which is caused by a repeat contraction and/or variants in chromatin modifiers essential for a repressive D4Z4 chromatin structure in somatic cells. In ICF there is hypomethylation of centromeric repeats, which is caused by recessive variants in one of four ICF genes, of which two are established chromatin modifiers. In this thesis, the mutation spectrum of FSHD and ICF has been expanded. The SMCHD1 mutation spectrum in FSHD2 has been expanded with the discovery of exonic SMCHD1 variants, intronic SMCHD1 variants, and whole SMCHD1 gene deletions. In addition, we identified heterozygous variants in a new FSHD2 gene, DNMT3B, in two FSHD2 families. For ICF syndrome we expanded the mutation spectrum in the two most common ICF genes, DNMT3B and ZBTB24. Show less
Boogaard, M.L. van den; Thijssen, P.E.; Aytekin, C.; Licciardi, F.; Kiykim, A.A.; Spossito, L.; ... ; Maarel, S.M. van der 2017
