Laminin alpha1 chain reduces muscular dystrophy in laminin alpha2 chain deficient mice.
Laminin (LN) alpha2 chain deficiency in humans and mice leads to severe forms of congenital muscular dystrophy (CMD). Here, we investigated whether LNalpha1 chain in mice can compensate for the absence of LNalpha2 chain and prevent the development of muscular dystrophy. We generated mice expressing a LNalpha1 chain transgene in skeletal muscle of LNalpha2 chain deficient mice. LNalpha1 is not normally expressed in muscle, but the transgenically produced LNalpha1 chain was incorporated into muscle basement membranes, and normalized the compensatory changes of expression of certain other laminin chains (alpha4, beta2). In 4-month-old mice, LNalpha1 chain could fully prevent the development of muscular dystrophy in several muscles, and partially in others. The LNalpha1 chain transgene not only reversed the appearance of histopathological features of the disease to a remarkable degree, but also greatly improved health and longevity of the mice. Correction of LNalpha2 chain deficiency by LNalpha1 chain may serve as a paradigm for gene therapy of CMD in patients.
Gawlik
Kinga
K
Department of Cell and Molecular Biology, Section of Cell and Developmental Biology, University of Lund, Sweden.
Miyagoe-Suzuki
Yuko
Y
Ekblom
Peter
P
Takeda
Shin'ichi
S
Durbeej
Madeleine
M
D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods; D005838:Genotype; D007797:Laminin / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes / Q000235:genetics
D017931:DNA Primers; D007797:Laminin; C102645:laminin alpha 2; C084098:laminin A