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1.
J Muscle Res Cell Motil ; 21(4): 345-55, 2000 May.
Article in English | MEDLINE | ID: mdl-11032345

ABSTRACT

Myosin heavy chain (MyHC) is the major contractile protein of muscle. We report the first complete cosmid cloning and definitive physical map of the tandemly linked human skeletal MyHC genes at 17p13.1. The map provides new information on the order, size, and relative spacing of the genes. and it resolves uncertainties about the two fastest twitch isoforms. The physical order of the genes is demonstrated to contrast with the temporal order of their developmental expression. Furthermore, nucleotide sequence comparisons allow an approximation of the relative timing of five ancestral duplications that created distinct genes for the six isoforms. A firm foundation is provided for molecular analysis in patients with suspected primary skeletal myosinopathies and for detailed modelling of the hypervariable surface loops which dictate myosin's kinetic properties.


Subject(s)
Muscle, Skeletal/embryology , Myosin Heavy Chains/genetics , 3' Untranslated Regions , Amino Acid Sequence , Base Sequence , Chromosome Mapping , Cloning, Molecular , Cosmids , Exons , Humans , Molecular Sequence Data , Muscle Development , Muscle, Skeletal/growth & development , Muscular Diseases/genetics , Oculomotor Muscles/embryology , Oculomotor Muscles/growth & development , Protein Isoforms/genetics , Sarcomeres/chemistry , Sequence Alignment
2.
Nat Med ; 5(4): 439-43, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10202936

ABSTRACT

Limb-girdle muscular dystrophies 2C-F represent a family of autosomal recessive diseases caused by defects in sarcoglycan genes. The cardiomyopathic hamster is a naturally occurring model for limb-girdle muscular dystrophy caused by a primary deficiency in delta-sarcoglycan. We show here that acute sarcolemmal disruption occurs in this animal model during forceful muscle contraction. A recombinant adeno-associated virus vector encoding human delta-sarcoglycan conferred efficient and stable genetic reconstitution in the adult cardiomyopathic hamster when injected directly into muscle. A quantitative assay demonstrated that vector-transduced muscle fibers are stably protected from sarcolemmal disruption; there was no associated inflammation or immunologic response to the vector-encoded protein. Efficient gene transduction with rescue of the sarcoglycan complex in muscle fibers of the distal hindlimb was also obtained after infusion of recombinant adeno-associated virus into the femoral artery in conjunction with histamine-induced endothelial permeabilization. This study provides a strong rationale for the development of gene therapy for limb-girdle muscular dystrophy.


Subject(s)
Cytoskeletal Proteins/therapeutic use , Genetic Therapy/methods , Histamine/therapeutic use , Membrane Glycoproteins/therapeutic use , Muscular Dystrophy, Animal/therapy , Animals , Cell Membrane Permeability , Cricetinae , Cytoskeletal Proteins/genetics , Dependovirus/genetics , Genetic Vectors , Humans , Membrane Glycoproteins/genetics , Perfusion , Rats , Rats, Inbred F344 , Recombinant Proteins/therapeutic use , Sarcoglycans , Sarcolemma/pathology
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