Laminin alpha1 chain reduces muscular dystrophy in laminin alpha2 chain deficient mice

Hum Mol Genet. 2004 Aug 15;13(16):1775-84. doi: 10.1093/hmg/ddh190. Epub 2004 Jun 22.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basement Membrane / metabolism
  • DNA Primers
  • Fluorescent Antibody Technique
  • Gene Expression Regulation*
  • Genetic Therapy / methods
  • Genotype
  • Laminin / deficiency*
  • Laminin / genetics*
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / ultrastructure
  • Muscular Dystrophies / genetics*
  • Muscular Dystrophies / metabolism*
  • Muscular Dystrophies / pathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transgenes / genetics

Substances

  • DNA Primers
  • Laminin
  • laminin alpha 2
  • laminin A