Résumé :
|
Facioscapulohumeral muscular dystrophy (FSHD) affects 1:20,000 people world wide. FSHD is clinically characterized by a progressive weakness and wasting of the facial, shoulder and upper arm muscles. Non-muscular symptoms may include sensorineural deafness and retinovasculopathy. In the large majority of patients, FSHD is caused by contraction of the D4Z4 repeat on chromosome 4q35. This contraction needs to occur in permissive genetic backgrounds of this chromosome to cause disease symptoms as contractions on non-permissive genetic backgrounds are non-pathogenic. Contractions to a repeat of 1-10 units is associated with a local chromatin relaxation of D4Z4 and the transcriptional derepression of the DUX4 gene encoding for a toxic double homeodomain protein. Only on permissive chromosomes the DUX4 transcript is sufficiently stabilized by a polyadenylation signal outside the repeat resulting in high amounts of DUX4 protein in 1;1,000 myonuclei in cell culture. In non permissive backgrounds, specific SNPs within the DUX4 polyadenylation signal prevent the DUX4 transcript from being stabilized. DUX4 is a conserved retrogene suggesting that it has a functional role in normal cells. DUX4 is indeed expressed at high levels in the germ line but its exact function in the germ line and its dysfunction in FSHD muscle are currently not known. Altogether these data support a model in which the DUX4 retrogene has a normal function in the germ line, while it is epigenetically silenced in somatic cells with incomplete repression in FSHD myonuclei. Attempts to generate transgenic mice expressing (inducible) DUX4 have proven difficult, likely because of its toxicity. We report on the generation of a transgenic mouse model carrying D4Z4 units isolated from a patient allele that expresses DUX4 and recapitulates all genetic, epigenetic and DUX4 expression attributes of FSHD, including high DUX4 expression levels in the germ line and the characteristic bursts of DUX4 expression in 1;1,000 muscle nuclei. These transgenic mice represent a new animal model for FSHD which can be used to study the molecular mechanisms underlying FSHD and to test new therapeutic intervention strategies.
|