Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models

W Kuang; H Xu; P H Vachon; L Liu; F Loechel; Ulla M. Wewer; E Engvall

doi:10.1172/JCI3705

Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models

W Kuang, H Xu, P H Vachon, L Liu, F Loechel, Ulla M. Wewer, E Engvall

158 Citationer (Scopus)

Abstract

Humans and mice with deficiency of the alpha2 subunit of the basement membrane protein laminin-2/merosin suffer from merosin-deficient congenital muscular dystrophy (MCMD). We have expressed a human laminin alpha2 chain transgene under the regulation of a muscle-specific creatine kinase promoter in mice with complete or partial deficiency of merosin. The transgene restores the synthesis and localization of merosin in skeletal muscle, and greatly improves muscle morphology and integrity and the health and longevity of the mice. However, the transgenic mice share with the nontransgenic dystrophic mice a progressive lameness of hind legs, suggestive of a nerve defect. These results indicate that the absence of merosin in tissues other than the muscle, such as nervous tissue, is a critical component of MCMD. Future gene therapies of human MCMD, and perhaps of other forms of muscular dystrophy, may require restoration of the defective gene product in multiple tissues.

Originalsprog	Engelsk
Tidsskrift	Journal of Clinical Investigation
Vol/bind	102
Udgave nummer	4
Sider (fra-til)	844-52
Antal sider	9
ISSN	0021-9738
DOI	https://doi.org/10.1172/JCI3705
Status	Udgivet - 1998

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10.1172/JCI3705

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@article{16629a3c2cf94690bc1a9ff5f3fdf889,

title = "Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models",

abstract = "Humans and mice with deficiency of the alpha2 subunit of the basement membrane protein laminin-2/merosin suffer from merosin-deficient congenital muscular dystrophy (MCMD). We have expressed a human laminin alpha2 chain transgene under the regulation of a muscle-specific creatine kinase promoter in mice with complete or partial deficiency of merosin. The transgene restores the synthesis and localization of merosin in skeletal muscle, and greatly improves muscle morphology and integrity and the health and longevity of the mice. However, the transgenic mice share with the nontransgenic dystrophic mice a progressive lameness of hind legs, suggestive of a nerve defect. These results indicate that the absence of merosin in tissues other than the muscle, such as nervous tissue, is a critical component of MCMD. Future gene therapies of human MCMD, and perhaps of other forms of muscular dystrophy, may require restoration of the defective gene product in multiple tissues.",

keywords = "Animals, Creatine Kinase, Disease Models, Animal, Gene Expression, Gene Targeting, Gene Therapy, Hindlimb, Humans, Laminin, Longevity, Mice, Mice, Mutant Strains, Mice, Transgenic, Muscle, Skeletal, Muscular Dystrophy, Animal, Transgenes",

author = "W Kuang and H Xu and Vachon, {P H} and L Liu and F Loechel and Wewer, {Ulla M.} and E Engvall",

year = "1998",

doi = "10.1172/JCI3705",

language = "English",

volume = "102",

pages = "844--52",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "4",

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TY - JOUR

T1 - Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models

AU - Kuang, W

AU - Xu, H

AU - Vachon, P H

AU - Liu, L

AU - Loechel, F

AU - Wewer, Ulla M.

AU - Engvall, E

PY - 1998

Y1 - 1998

N2 - Humans and mice with deficiency of the alpha2 subunit of the basement membrane protein laminin-2/merosin suffer from merosin-deficient congenital muscular dystrophy (MCMD). We have expressed a human laminin alpha2 chain transgene under the regulation of a muscle-specific creatine kinase promoter in mice with complete or partial deficiency of merosin. The transgene restores the synthesis and localization of merosin in skeletal muscle, and greatly improves muscle morphology and integrity and the health and longevity of the mice. However, the transgenic mice share with the nontransgenic dystrophic mice a progressive lameness of hind legs, suggestive of a nerve defect. These results indicate that the absence of merosin in tissues other than the muscle, such as nervous tissue, is a critical component of MCMD. Future gene therapies of human MCMD, and perhaps of other forms of muscular dystrophy, may require restoration of the defective gene product in multiple tissues.

AB - Humans and mice with deficiency of the alpha2 subunit of the basement membrane protein laminin-2/merosin suffer from merosin-deficient congenital muscular dystrophy (MCMD). We have expressed a human laminin alpha2 chain transgene under the regulation of a muscle-specific creatine kinase promoter in mice with complete or partial deficiency of merosin. The transgene restores the synthesis and localization of merosin in skeletal muscle, and greatly improves muscle morphology and integrity and the health and longevity of the mice. However, the transgenic mice share with the nontransgenic dystrophic mice a progressive lameness of hind legs, suggestive of a nerve defect. These results indicate that the absence of merosin in tissues other than the muscle, such as nervous tissue, is a critical component of MCMD. Future gene therapies of human MCMD, and perhaps of other forms of muscular dystrophy, may require restoration of the defective gene product in multiple tissues.

KW - Animals

KW - Creatine Kinase

KW - Disease Models, Animal

KW - Gene Expression

KW - Gene Targeting

KW - Gene Therapy

KW - Hindlimb

KW - Humans

KW - Laminin

KW - Longevity

KW - Mice

KW - Mice, Mutant Strains

KW - Mice, Transgenic

KW - Muscle, Skeletal

KW - Muscular Dystrophy, Animal

KW - Transgenes

U2 - 10.1172/JCI3705

DO - 10.1172/JCI3705

M3 - Journal article

C2 - 9710454

SN - 0021-9738

VL - 102

SP - 844

EP - 852

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 4

ER -

Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models

Abstract

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