Studies of the epigenetic disease mechanism in FSHD

Greef, J.C. de (2009)

Doctoral Thesis

Facioscapulohumeral muscular dystrophy is an autosomal dominant myopathy that is caused by a contraction of the D4Z4 repeat on the 4qA161 genetic variant of chromosome 4qter (FSHD1). FSHD1 patients show loss of DNA methylation on the first D4Z4 repeat unit. Interestingly, a small group of patients with a myopathy clinically indistinguishable from FSHD1 but without a D4Z4 contraction (FSHD2) and patients suffering from the ICF (Immunodeficiency, Centromeric instability and Facial anomalies) syndrome also present with very low D4Z4 methylation. In this thesis studies are described that focused on the unraveling of the epigenetic disease mechanism responsible for FSHD development. These studies show that (1) the overlap between FSHD patients and ICF patients is restricted to low D4Z4 methylation levels, (2) FSHD1 and FSHD2 patients show loss of methyl groups on lysine 9 of histone protein H3 and a secondary loss of the proteins HP1? and cohesin at the D4Z4 repeat, (3) the combination of the 4qA161 genetic variant and low D4Z4 methylation is a necessary prerequisite for FSHD development and (4) supplementation with folic and methionine can raise the total amount of methyl groups present on the DNA but cannot restore D4Z4 methylation levels in FSHD1 and FSHD2 patients.

• D4Z4
• DNA methylation
• Epigenetics
• FSHD
• H3K9me3
• ICF syndrome
• Immunodeficiency
• Myopathy

• All authors: Greef, J.C. de
• Supervisor: Frants, R.R.; Maarel, S.M. van der
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden University Medical Center (LUMC), Leiden University
• Date: 2009-11-19
• ISBN (print): 9789090245218