Facioscapulohumeral muscular dystrophy (FSHD) is a common myopathy in adults and is caused by partial deletion of the D4Z4 repeat in the subtelomere of chromosome 4q of most patients. There is no cure or effective treatment for FSHD and its complex genetic and epigenetic etiology has long precluded elucidation of its pathophysiology. This limited knowledge of FSHD disease mechanism has hampered our ability to develop validated cellular and animal models faithfully representing the disease. Taking advantage of the high frequency of somatic mosaicism observed in FSHD, and recent advances in human myoblast immortalization, we aim to generate immortalized clonal isogenic myogenic cell lines that only differ by the presence or absence of the mutation. More specifically, from each of the 5 mosaic FSHD patients we have identified, we will generate 5 pairs of clones, one set with and one set without mutation. These cell lines will be characterized at the genetic (D4Z4 repeat array constitution), epigenetic (chromatin structure of D4Z4), transcriptional (expression of FSHD candidate genes, most notably DUX4), morphological (presence of a vacuolar or necrotic phenotype) and functional level (sensitivity to oxidative stress and ability to participate in muscle differentiation in vivo and in vitro). The principal advantage of these isogenic clones, differing only in the presence or absence of the FSHD mutation, is the ability to do paired comparisons that identify only FSHD-specific differences. This feature of the isogenic clones will greatly facilitate our final aim of generating a molecular signature for FSHD by deep transcriptome sequencing. We hypothesize that their immortality, isogenicity and myogenic origin will make them ideal cell lines to advance our understanding of the pathophysiology of FSHD and, in combination with the establishment of a molecular signature for FSHD, for high throughput drug screens. Therefore, the long-term goal is to generate a faithful myogenic cell model that can be applied in high throughput small molecule screens for FSHD.

Public Health Relevance

This project aims to generate immortalized muscle cell lines of FSHD patients that are isogenic. This means that they are genetically identical except for the mutation. We expect that these cell lines will aid the understanding of the disease mechanism and will be useful for small molecule screens for therapeutic purposes.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
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Leiden University Medical Center
Zip Code
2333 -ZA
Sacconi, Sabrina; CamaƱo, Pilar; de Greef, Jessica C et al. (2012) Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity. J Med Genet 49:41-6
Krom, Yvonne D; Dumonceaux, Julie; Mamchaoui, Kamel et al. (2012) Generation of isogenic D4Z4 contracted and noncontracted immortal muscle cell clones from a mosaic patient: a cellular model for FSHD. Am J Pathol 181:1387-401
van der Maarel, Silvere M; Tawil, Rabi; Tapscott, Stephen J (2011) Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Trends Mol Med 17:252-8