[Current status and future prospects of research on Fukuyama muscular dystrophy].
Fukuyama congenital muscular dystrophy(FCMD) is a second common childhood muscular dystrophy in Japan. All FCMD patients have ancestral insertion of the SVA retrotransposal element into fukutin. We show that aberrant mRNA splicing induced by SVA exon-trapping caused FCMD. Introduction of 3 cocktailed antisense oligonucleotides(AONs) targeting around these splice sites prevented pathogenic splicing in FCMD patient cells and model mice, and normalized protein production and functions of Fukutin as well as O-glycosylation of α-dystroglycan. We show the promise of splicing modulation therapy as the first radical clinical treatment for FCMD in the near future. We also show that fukutin is prerequisite to ameliorate muscular dystrophic phenotype by myofiber-selective LARGE expression. Recent advances in FCMD are discussed.
Tatsushi
T
Toda
D000818:Animals; D002675:Child, Preschool; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods / Q000639:trends; D006031:Glycosylation; D006801:Humans; D007223:Infant; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D020320:Oligoribonucleotides, Antisense; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D012106:Research / Q000639:trends*; D058494:Walker-Warburg Syndrome / Q000145:classification / Q000235:genetics / Q000628:therapy
C483081:DAG1 protein, human; C113587:FKTN protein, human; D008565:Membrane Proteins; D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; D049030:Dystroglycans; C117674:LARGE1 protein, human; D017351:N-Acetylglucosaminyltransferases