Disease relevance of Lama2

• Murine muscular dystrophy caused by a mutation in the laminin alpha 2 (Lama2) gene [1].
• Bax inactivation also improved postnatal growth rate and myofiber histology and decreased fixed contractures of Lama2(-/-) mice [2].
• Our results indicate that merosin deficiency may be the primary defect in dy mice and suggest that a disruption of the link between alpha-dystroglycan and merosin may be involved in the pathogenesis of muscle degeneration and peripheral neuropathy in dy mice [3].
• Using a reporter construct, the short-term efficacy of fiber transduction reached 40% and was similar in wild-type, dy/dy and dy(2J)/dy(2J) animals, indicating that ongoing muscle fibrosis was not a major obstacle to the electrotransfer-mediated gene transfer [4].
• Humans with merosin-deficient congenital muscular dystrophy have both sucking problems during infancy and sleep-disordered breathing during childhood [5].

Psychiatry related information on Lama2

• The dy/dy mice demonstrated elevated auditory thresholds ranging from 25 to 27 dB at each frequency tested (p<0.0001) [6].

High impact information on Lama2

• Using recombinant fragments of LN-alpha2 (rLN-alpha2), the M. leprae-binding site was localized to the G domain. rLN-alpha2G mediated M. leprae binding to cell lines and to sciatic nerves of dystrophic dy/dy mice lacking LN-alpha2, but expressing laminin receptors [7].
• 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 [8].
• 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 [8].
• Analyses of integrins showed an abnormal expression and localization of alpha7beta1 isoforms in myofibers of merosin-deficient human patients and mice, but not in dystrophin-deficient or sarcoglycan-deficient humans and animals [9].
• Mutations in genes coding for dystrophin, for alpha, beta, gamma, and delta-sarcoglycans, or for the alpha2 chain of the basement membrane component merosin (laminin-2/4) cause various forms of muscular dystrophy [9].

Chemical compound and disease context of Lama2

• We furthermore assessed Evans blue incorporation in skeletal muscle of the dystrophia muscularis (dy/dy) mouse and its milder allelic variant, the dy2J/dy2J mouse, animal models for congenital muscular dystrophy [10].
• In contrast, the levels of alpha7beta1 integrin are severely diminished in patients with laminin alpha2 chain congenital dystrophy muscular dystrophy and in dy/dy mice that also do not make the alpha2 laminin chain [11].
• The mer receptor tyrosine kinase mediates phagocytosis of apoptotic cells and modulates cytokine production; it is also required for prevention of systemic autoimmune disease [12].

Biological context of Lama2

• We then used cross-breeding to introduce the transgenes into diseased mdx or Lama2-null mice [13].
• Lama2 mutant mice have thin dentin and a widely opened dentinal tube, as compared with wild-type and heterozygote mice, which is similar to the phenotype of dentinogenesis imperfecta [14].
• Assignment of laminin alpha 2-chain gene (Lama2) to mouse chromosome 10A4-B1 by fluorescence in situ hybridization [15].
• Tissue distribution of the dystrophin-related gene product and expression in the mdx and dy mouse [16].
• Deficiency of merosin in dystrophic dy mice and genetic linkage of laminin M chain gene to dy locus [3].

Anatomical context of Lama2

• Here, we demonstrate a critical role for LN-2 in CNS myelination by showing that dy/dy mice have quantitative and morphologic defects in CNS myelin [17].
• Merosin is the predominant laminin isoform in the basal lamina of striated muscle and peripheral nerve, and consists of M, B1 or S, and B2 chains [3].
• Analysis of merosin expression of dystrophic dy mice revealed a specific deficiency of merosin in skeletal muscle, cardiac muscle, and peripheral nerve [3].
• Muscular dystrophy by merosin deficiency decreases acetylcholinesterase activity in thymus of Lama2dy mice [18].
• Moreover, merosin molecules exist as the short fine cross-bridge fibrils connecting the basal lamina to the neighboring outer leaflet of the muscle plasma membrane [19].

Associations of Lama2 with chemical compounds

• The binding of laminin and merosin is Ca2+ dependent and is inhibited by NaCl and heparin [20].
• Binding was inhibited by antibodies recognizing VLA alpha 6 or beta 1, suggesting that the VLA-6 integrin is a merosin receptor [21].
• Thirty-one mer phosphorothioate oligodeoxynucleotide complementary to the SES of dystrophin exon 19 was intraperitoneally administered to mdx mice without any carrier [22].
• We find that induction of AChR clustering in C2 myotubes is specific for laminin-1; neither laminin-2 (merosin) nor laminin-11 (a synapse-specific isoform) are active [23].
• The potassium-channel blocker, 3,4-diaminopyridine, increased force of dy/dy sternohyoid muscle during twitch and 25-Hz contractions by 148 +/- 20% (p < 0.00001) and 109 +/- 18% (p < 0.00002), respectively [5].

Physical interactions of Lama2

• Biochemical analysis demonstrates that the 120 kDa peripheral nerve alpha-dystroglycan binds merosin as well as laminin [20].

Regulatory relationships of Lama2

• Differential heparin sensitivity of alpha-dystroglycan binding to laminins expressed in normal and dy/dy mouse skeletal muscle [24].
• In addition to laminin-1, merosin (laminin-2/4) is present both before and after formation of neuromuscular junctions and also promotes AChR clustering and colocalization with the integrin as well as synergism with agrin [25].
• Overexpression of the apoptosis-suppressing molecule Bcl-2 also promoted the survival of merosin-deficient myotubes, but did not restore a normal expression of alpha7beta1D integrins [9].
• Relationship between neuronal migration and cell-substratum adhesion: laminin and merosin promote olfactory neuronal migration but are anti-adhesive [26].

Other interactions of Lama2

• Studies with antisera raised against a DMDL fusion protein identify a 400,000 Mr protein in all mouse tissues tested, including those of mdx and dy mice [16].
• The interaction between alpha-dystroglycan and merosin may play a role in the regulation of Schwann cell myelination and/or maintenance of myelin sheath [20].
• Analysis of RNA from the hindlimbs of dy/dy mice demonstrated that in the absence of laminin alpha7 gene transcription is inhibited and limited to specific alternatively spliced isoforms [11].
• Elimination of myostatin does not combat muscular dystrophy in dy mice but increases postnatal lethality [27].
• In the present study, we tested the effect of overexpressing ADAM12 in dy(W) laminin-deficient mice. dy mice have a very severe clinical phenotype and would be expected to benefit greatly from enhanced regeneration [28].

Analytical, diagnostic and therapeutic context of Lama2

• We found that both of these genetic interventions produced a several-fold increase in the lifespan of Lama2(-/-) mice [2].
• The immunogold electron microscopy disclosed that the merosin was present at the innermost layer (lamina lucida) of the basal lamina of normal human skeletal myofibers [29].
• Using the RT-PCR assay, we demonstrate that merosin, but not laminin, is also expressed in the thymus [21].
• To gain greater insight into the biochemical and molecular events that link alpha2-laminin deficiency with muscle fiber necrosis, and the associated compensatory responses, gene expression profiles were characterized in diaphragm muscle from 8-wk-old dy/dy mice using oligonucleotide microarrays [30].
• Partial laminin alpha2 chain restoration in alpha2 chain-deficient dy/dy mouse by primary muscle cell culture transplantation [31].

References