The transgenic expression of LARGE exacerbates the muscle phenotype of dystroglycanopathy mice.
Mutations in fukutin-related protein (FKRP) underlie a group of muscular dystrophies associated with the hypoglycosylation of α-dystroglycan (α-DG), a proportion of which show central nervous system involvement. Our original FKRP knock-down mouse (FKRP(KD)) replicated many of the characteristics seen in patients at the severe end of the dystroglycanopathy spectrum but died perinatally precluding its full phenotyping and use in testing potential therapies. We have now overcome this by crossing FKRP(KD) mice with those expressing Cre recombinase under the Sox1 promoter. Owing to our original targeting strategy, this has resulted in the restoration of Fkrp levels in the central nervous system but not the muscle, thereby generating a new model (FKRP(MD)) which develops a progressive muscular dystrophy resembling what is observed in limb girdle muscular dystrophy. Like-acetylglucosaminyltransferase (LARGE) is a bifunctional glycosyltransferase previously shown to hyperglycosylate α-DG. To investigate the therapeutic potential of LARGE up-regulation, we have now crossed the FKRP(MD) line with one overexpressing LARGE and show that, contrary to expectation, this results in a worsening of the muscle pathology implying that any future strategies based upon LARGE up-regulation require careful management.
Comparative Biomedical Sciences, Royal Veterinary College, University of London, London NW1 0TU, UK.
Charlotte
C
Whitmore
Marta
M
Fernandez-Fuente
Helen
H
Booler
Callum
C
Parr
Manoli
M
Kavishwar
Attia
A
Ashraf
Erica
E
Lacey
Jihee
J
Kim
Rebecca
R
Terry
Mark R
MR
Ackroyd
Kim E
KE
Wells
Francesco
F
Muntoni
Dominic J
DJ
Wells
Susan C
SC
Brown
D000818:Animals; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D002490:Central Nervous System / Q000378:metabolism; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000378:metabolism*; D006031:Glycosylation; D007797:Laminin / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000096:biosynthesis* / Q000235:genetics*; D010430:Pentosyltransferases; D011506:Proteins / Q000235:genetics*; D014166:Transferases; D015854:Up-Regulation; D058494:Walker-Warburg Syndrome / Q000235:genetics* / Q000401:mortality
C501370:Lama4 protein, mouse; D007797:Laminin; D011506:Proteins; C102645:laminin alpha 2; D049030:Dystroglycans; D014166:Transferases; C502747:Large1 protein, mouse; D017351:N-Acetylglucosaminyltransferases; C499093:Fkrp protein, mouse; D010430:Pentosyltransferases