Facioscapulohumeral muscular dystrophy (FSHD) is the third most common myopathy, afflicting approximately one out of 20,000 people worldwide. The most characteristic symptom is a progressive atrophy of facial, shoulder and upper arm muscles. Additionally, over half of FSHD patients have abnormal blood vessels in the back of the eye, which causes vision problems in some patients.
Over 95% of FSHD cases carry a genetic abnormality within a series of DNA repeats at chromosome 4q35. Although the unaffected population contains between 11 and 150 copies of this DNA repeat (named D4Z4), FSHD patients have deletions resulting in between one and ten D4Z4 repeats. This mutation is not in a known protein-encoding gene, thus these deletions are expected to disrupt the normal regulation of gene expression. However, there is little agreement regarding which gene or genes are misregulated in FSHD, thus complicating the creation of appropriate FSHD animal models, and hindering advances in understanding and treating this disease. Previous studies demonstrate that altered expression of FRG1disrupts the musculature in developing Xenopus laevis, thus supporting a role for FRG1 in FSHD pathology.
In this study, the spatiotemporal expression of FRG1 is analyzed during Xenopus development, revealing prominent expression in the vasculature. The authors show that FRG1 is required for the growth of new blood vessels from pre-existing vessels, but is not needed for spontaneous blood vessel formation. Conversely, increasing FRG1 levels promotes angiogenesis and disrupts the organization of the developing vasculature. Thus, normal levels and patterns of FRG1 expression are crucial for proper vascularization.
This study, combined with previous work analyzing the effect of FRG1 on the developing musculature, demonstrates that FRG1 affects the skeletal musculature and the vasculature when its expression levels are altered in an animal model. Thus, FRG1 expression is a causal factor in FSHD pathology. Prominent expression of FRG1 in the vasculature suggests that future FSHD research should examine vascular cell types and tissue, as well as skeletal muscle.