Zebrafish models for human FKRP muscular dystrophies

• Published in: Human molecular genetics 2010-02, Vol.19 (4), p.623-633
• Main Authors: Kawahara, Genri, Guyon, Jeffrey R., Nakamura, Yukio, Kunkel, Louis M.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Danio rerio; Disease Models, Animal; Diseases of striated muscles. Neuromuscular diseases; Dystroglycans - metabolism; Eye - growth & development; Eye - metabolism; Freshwater; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Genetics of eukaryotes. Biological and molecular evolution; Glycosylation; Glycosyltransferases - genetics; Glycosyltransferases - metabolism; Humans; Laminin - metabolism; Medical sciences; Molecular and cellular biology; Muscle, Skeletal - metabolism; Muscular Dystrophies - congenital; Muscular Dystrophies - genetics; Muscular Dystrophies - metabolism; Neurology; Protein Binding; Proteins - genetics; Proteins - metabolism; Zebrafish - embryology; Zebrafish - genetics; Zebrafish - metabolism; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddp528

Various muscular dystrophies are associated with the defective glycosylation of α-dystroglycan and are known to result from mutations in genes encoding glycosyltransferases. Fukutin-related protein (FKRP) was identified as a homolog of fukutin, the defective protein in Fukuyama-type congenital muscular dystrophy (FCMD), that is thought to function as a glycosyltransferase. Mutations in FKRP have been linked to a variety of phenotypes including Walker–Warburg syndrome (WWS), limb girdle muscular dystrophy (LGMD) 2I and congenital muscular dystrophy 1C (MDC1C). Zebrafish are a useful animal model to reveal the mechanism of these diseases caused by mutations in FKRP gene. Downregulating FKRP expression in zebrafish by two different morpholinos resulted in embryos which had developmental defects similar to those observed in human muscular dystrophies associated with mutations in FKRP. The FKRP morphants showed phenotypes involving alterations in somitic structure and muscle fiber organization, as well as defects in developing eye morphology. Additionally, they were found to have a reduction in α-dystroglycan glycosylation and a shortened myofiber length. Moreover, co-injection of fish or human FKRP mRNA along with the morpholino restored normal development, α-dystroglycan glycosylation and laminin binding activity of α-dystroglycan in the morphants. Co-injection of the human FKRP mRNA containing causative mutations found in human patients of WWS, MDC1C and LGMD2I could not restore their phenotypes significantly. Interestingly, these morphant fish having human FKRP mutations showed a wide phenotypic range similar to that seen in humans.