TY - JOUR

T1 - Laminin alpha2 deficiency and muscular dystrophy; genotype-phenotype correlation in mutant mice

AU - Guo, L T

AU - Zhang, X U

AU - Kuang, W

AU - Xu, Hong

AU - Liu, L A

AU - Vilquin, J-T

AU - Miyagoe-Suzuki, Y

AU - Takeda, S

AU - Ruegg, M A

AU - Wewer, U M

AU - Engvall, E

PY - 2003/3/1

Y1 - 2003/3/1

N2 - Deficiency of laminin alpha2 is the cause of one of the most severe muscular dystrophies in humans and other species. It is not yet clear how particular mutations in the laminin alpha2 chain gene affect protein expression, and how abnormal levels or structure of the protein affect disease. Animal models may be valuable for such genotype-phenotype analysis and for determining mechanism of disease as well as function of laminin. Here, we have analyzed protein expression in three lines of mice with mutations in the laminin alpha2 chain gene and in two lines of transgenic mice overexpressing the human laminin alpha2 chain gene in skeletal muscle. The dy(3K)/dy(3K) experimental mutant mice are completely deficient in laminin alpha2; the dy/dy spontaneous mutant mice have small amounts of apparently normal laminin; and the dy(W)/dy(W) mice express even smaller amounts of a truncated laminin alpha2, lacking domain VI. Interestingly, all mutants lack laminin alpha2 in peripheral nerve. We have demonstrated previously, that overexpression of the human laminin alpha2 in skeletal muscle in dy(2J)/dy(2J) and dy(W)/dy(W) mice under the control of a striated muscle-specific creatine kinase promoter substantially prevented the muscular dystrophy in these mice. However, dy(W)/dy(W) mice, expressing the human laminin alpha2 under the control of the striated muscle-specific portion of the desmin promoter, still developed muscular dystrophy. This failure to rescue is apparently because of insufficient production of laminin alpha2. This study provides additional evidence that the amount of laminin alpha2 is most critical for the prevention of muscular dystrophy. These data may thus be of significance for attempts to treat congenital muscular dystrophy in human patients.

AB - Deficiency of laminin alpha2 is the cause of one of the most severe muscular dystrophies in humans and other species. It is not yet clear how particular mutations in the laminin alpha2 chain gene affect protein expression, and how abnormal levels or structure of the protein affect disease. Animal models may be valuable for such genotype-phenotype analysis and for determining mechanism of disease as well as function of laminin. Here, we have analyzed protein expression in three lines of mice with mutations in the laminin alpha2 chain gene and in two lines of transgenic mice overexpressing the human laminin alpha2 chain gene in skeletal muscle. The dy(3K)/dy(3K) experimental mutant mice are completely deficient in laminin alpha2; the dy/dy spontaneous mutant mice have small amounts of apparently normal laminin; and the dy(W)/dy(W) mice express even smaller amounts of a truncated laminin alpha2, lacking domain VI. Interestingly, all mutants lack laminin alpha2 in peripheral nerve. We have demonstrated previously, that overexpression of the human laminin alpha2 in skeletal muscle in dy(2J)/dy(2J) and dy(W)/dy(W) mice under the control of a striated muscle-specific creatine kinase promoter substantially prevented the muscular dystrophy in these mice. However, dy(W)/dy(W) mice, expressing the human laminin alpha2 under the control of the striated muscle-specific portion of the desmin promoter, still developed muscular dystrophy. This failure to rescue is apparently because of insufficient production of laminin alpha2. This study provides additional evidence that the amount of laminin alpha2 is most critical for the prevention of muscular dystrophy. These data may thus be of significance for attempts to treat congenital muscular dystrophy in human patients.

KW - Animals

KW - DNA Mutational Analysis

KW - Desmin

KW - Disease Models, Animal

KW - Fluorescent Antibody Technique

KW - Gene Expression

KW - Genotype

KW - Humans

KW - Immunoblotting

KW - Laminin

KW - Mice

KW - Mice, Mutant Strains

KW - Mice, Transgenic

KW - Muscle, Skeletal

KW - Muscular Dystrophies

KW - Peripheral Nerves

KW - Phenotype

KW - Promoter Regions, Genetic

KW - Protein Structure, Tertiary

KW - Protein Subunits

KW - Recombinant Fusion Proteins

M3 - Journal article

C2 - 12609502

VL - 13

SP - 207

EP - 215

JO - Journal of Neuromuscular Diseases

JF - Journal of Neuromuscular Diseases

SN - 0960-8966

IS - 3

ER -