title: Reduced expression of fukutin related protein in mice results in a model for fukutin related protein associated muscular dystrophies.
abstract: Mutations in fukutin related protein (FKRP) are responsible for a common group of muscular dystrophies ranging from adult onset limb girdle muscular dystrophies to severe congenital forms with associated structural brain involvement, including Muscle Eye Brain disease. A common feature of these disorders is the variable reduction in the glycosylation of skeletal muscle alpha-dystroglycan. In order to gain insight into the pathogenesis and clinical variability, we have generated two lines of mice, the first containing a missense mutation and a neomycin cassette, FKRP-Neo(Tyr307Asn) and the second containing the FKRP(Tyr307Asn) mutation alone. We have previously associated this missense mutation with a severe muscle-eye-brain phenotype in several families. Homozygote Fkrp-Neo(Tyr307Asn) mice die soon after birth and show a reduction in the laminin-binding epitope of alpha-dystroglycan in muscle, eye and brain, and have reduced levels of FKRP transcript. Homozygous Fkrp(Tyr307Asn) mice showed no discernible phenotype up to 6 months of age, contrary to the severe clinical course observed in patients with the same mutation. These results suggest the generation of a mouse model for FKRP related muscular dystrophy requires a knock-down rather than a knock-in strategy in order to give rise to a disease phenotype.
authors.affiliation: Department of Cellular and Molecular Neuroscience, Hammersmith Hospital, Imperial College, London, UK.
authors.forename: M R
authors.initials: MR
authors.lastname: Ackroyd
authors.forename: L
authors.initials: L
authors.lastname: Skordis
authors.forename: M
authors.initials: M
authors.lastname: Kaluarachchi
authors.forename: J
authors.initials: J
authors.lastname: Godwin
authors.forename: S
authors.initials: S
authors.lastname: Prior
authors.forename: M
authors.initials: M
authors.lastname: Fidanboylu
authors.forename: R J
authors.initials: RJ
authors.lastname: Piercy
authors.forename: F
authors.initials: F
authors.lastname: Muntoni
authors.forename: S C
authors.initials: SC
authors.lastname: Brown
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D002465:Cell Movement; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D002678:Chimera; D049030:Dystroglycans / Q000378:metabolism; D005260:Female; D018390:Gene Targeting; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D023421:Models, Animal; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020125:Mutation, Missense; D010430:Pentosyltransferases; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014166:Transferases
chemical_list: D011506:Proteins; D049030:Dystroglycans; D014166:Transferases; C499093:Fkrp protein, mouse; D010430:Pentosyltransferases