The peripheral retinal vascular abnormality which accompanies FSHD belongs morphologically and clinically to a class of developmental 'retinal hypovasculopathies' caused by abnormalities of 'Wnt' signalling, which controls retinal angiogenesis. Wnt signalling is also fundamental to myogenesis. This paper integrates modern concepts of myogenic cell signalling and of transcription factor expression and control with data from the classic early ophthalmic and myology embryology literature. Together, they support an hypothesis that abnormalities of Wnt signalling, which activates myogenic programs and transcription factors in myoblasts and satellite cells, leads to defective muscle regeneration in FSHD. The selective vulnerability of different FSHD muscles (notably facial muscle, from the second branchial arch) might reflect patterns of transcription factor redundancies. This hypothesis has implications for FSHD research through study of transcription factors patterning in normal human muscles, and for autologous cell transplantation.
"That morphological phenotype might be due to FSHD myoblasts being more sensitive to stress than analogous controls. Because we used only moderately affected muscle to generate myoblast cell strains and FSHD is characteristically a slowly progressive disease in which disease muscle biopsies look relatively normal at the time of clinical onset , the normal appearance of FSHD myoblasts and myotubes under our optimized growth conditions is likely to be relevant to understanding pathogenesis. Moreover, the equally good generation, propagation, growth, and differentiation of FSHD and control myoblasts also argue against the possibility that we selected a non-representative sub-phenotype of FSHD myoblasts. "
[Show abstract][Hide abstract] ABSTRACT: Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contraction of an array of tandem 3.3-kb repeats (D4Z4) at 4q35. Within each repeat unit is a gene, DUX4, that can encode a protein containing two homeodomains. A DUX4 transcript derived from the last repeat unit in a contracted array is associated with pathogenesis but it is unclear how.
Using exon-based microarrays, the expression profiles of myogenic precursor cells were determined. Both undifferentiated myoblasts and myoblasts differentiated to myotubes derived from FSHD patients and controls were studied after immunocytochemical verification of the quality of the cultures. To further our understanding of FSHD and normal myogenesis, the expression profiles obtained were compared to those of 19 non-muscle cell types analyzed by identical methods.
Many of the ~17,000 examined genes were differentially expressed (>2-fold, p<0.01) in control myoblasts or myotubes vs. non-muscle cells (2185 and 3006, respectively) or in FSHD vs. control myoblasts or myotubes (295 and 797, respectively). Surprisingly, despite the morphologically normal differentiation of FSHD myoblasts to myotubes, most of the disease-related dysregulation was seen as dampening of normal myogenesis-specific expression changes, including in genes for muscle structure, mitochondrial function, stress responses, and signal transduction. Other classes of genes, including those encoding extracellular matrix or pro-inflammatory proteins, were upregulated in FSHD myogenic cells independent of an inverse myogenesis association. Importantly, the disease-linked DUX4 RNA isoform was detected by RT-PCR in FSHD myoblast and myotube preparations only at extremely low levels. Unique insights into myogenesis-specific gene expression were also obtained. For example, all four Argonaute genes involved in RNA-silencing were significantly upregulated during normal (but not FSHD) myogenesis relative to non-muscle cell types.
DUX4's pathogenic effect in FSHD may occur transiently at or before the stage of myoblast formation to establish a cascade of gene dysregulation. This contrasts with the current emphasis on toxic effects of experimentally upregulated DUX4 expression at the myoblast or myotube stages. Our model could explain why DUX4's inappropriate expression was barely detectable in myoblasts and myotubes but nonetheless linked to FSHD.
BMC Medical Genomics 09/2011; 4(1):67. DOI:10.1186/1755-8794-4-67 · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent advances have provided a model for understanding the underlying molecular genetic changes in facioscapulohumeral muscular dystrophy (FSHD). This review will highlight our current understanding and future research directions.
FSHD typically results from contraction of a critical number of D4Z4 repeats in a macrosatellite repeat array on chromosome 4q35. Contraction leads to loss of DNA methylation and heterochromatin markers in the 4q35 D4Z4 region, resulting in relaxation of the chromatin structure and release of DUX4 repression. DUX4, a retrogene contained in the D4Z4 repeats, is normally epigenetically silenced in somatic cells. Stable expression of DUX4, however, can only occur in the presence of a permissive genetic background, which contains a polyadenylation signal sequence that stabilizes DUX4 mRNA. Expression of DUX4 mRNA and protein occurs at low frequency but in high abundance in FSHD myotube nuclei. DUX4 expression in transfection studies induces apoptosis and interferes with myogenesis.
FSHD results from a unique combination of genetic and epigenetic changes on 4q35 leading to release of repression of DUX4, causing disease in a toxic gain-of-function manner. Questions remain regarding the normal function of DUX4 and how expression of DUX4 in somatic cells leads to FSHD.
Current opinion in neurology 07/2011; 24(5):423-8. DOI:10.1097/WCO.0b013e32834959af · 5.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Facioscapulohumeral dystrophy (FSHD) is an autosomal-dominant disorder characterized by weakness of the face, upper arm, shoulder, and lower limb musculature, with an onset between the first and third decades. Coats disease is a congenital disorder of retinal vascular development characterized by unilateral peripheral retinal telangiectasia and progressive subretinal and intraretinal exudation. This condition has a predilection for children and is usually isolated. Retinal vascular changes similar to those seen in Coats disease have been demonstrated by fluorescein angiography in 40% to 75% of patients with FSHD. Most patients have asymptomatic retinal telangiectasia found at ocular screening in adulthood after diagnosis of FSHD. We report a 7-month-old infant with bilateral Coats-like retinopathy in which the eye disease was discovered before findings of FSHD were clinically evident. To our knowledge, this patient represents the youngest reported case of preclinical FSHD with ocular disease.
Journal of AAPOS: the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus 04/2012; 16(2):204-6. DOI:10.1016/j.jaapos.2011.11.005 · 1.00 Impact Factor
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