Disease relevance of Lamb2

• In transgenic Lamb2(-/-) mice, beta2 deposition in only glomeruli prevented proteinuria but did not ameliorate the severe phenotype [1].
• We conclude that muscle defects in Lamb2(-/-) mice are responsible for the severe failure to thrive phenotype, and that renal replacement therapy alone will be an inadequate treatment for Pierson syndrome [1].
• To investigate the GBM's role in glomerular filtration, we characterized GBM and overlying podocyte architecture in relation to development and progression of proteinuria in Lamb2-/- mice, which model Pierson syndrome, a rare congenital nephrotic syndrome [2].
• B6.yaa mice are not overtly autoimmune, but the addition of Sle1, which contains the autoimmune-predisposing Slam/Cd2 haplotype, causes the development of fatal lupus with numerous immunological aberrations [3].

High impact information on Lamb2

• S-laminin/laminin beta 2, a homologue of the widely distributed laminin B1/beta 1 chain, is a major component of adult renal glomerular basement membrane (GBM) [4].
• In this issue of the JCI, Jarad et al. show that in laminin beta2-deficient (Lamb2-/-) mice, proteinuria can be directly attributed to the altered composition of the GBM (see the related article beginning on page 2272) [5].
• Lamb2(-/-) mice are a model for Pierson syndrome; they exhibit defects in the kidney glomerular barrier, in the development and organization of the neuromuscular junction, and in the retina [1].
• N-CAM, 43K-rapsyn, and S-laminin mRNAs are concentrated at synaptic sites in muscle fibers [6].
• S-laminin: mapping to mouse chromosome 9 and expression in the linked mutants tippy and ducky [7].

Biological context of Lamb2

• Lamb2(-/-) mice fail to thrive and die very small at 3 weeks of age, but to what extent the kidney and neuromuscular defects each contribute to this severe phenotype has been obscure, though highly relevant to understanding Pierson syndrome [1].
• A significant association was found between postrestraint rearings during min 5 through 8 in the open field and the Lamb2 marker on chromosome 1 (r = .718, p < .0001) [8].

Anatomical context of Lamb2

• To investigate this, we generated transgenic mouse lines expressing rat laminin beta2 either in muscle or in glomerular epithelial cells (podocytes) and crossed them onto the Lamb2(-/-) background [1].
• Among NSC cell lines, only NSC-34 aggregates acetylcholine receptors on co-cultured myotube and expresses a receptor for S-laminin, a neuromuscular junction specific basal lamina protein [9].

Other interactions of Lamb2

• S-Laminin, a homologue of the laminin B1 chain, is present in a subset of basal laminae, including those of the skeletal neuromuscular junction and the renal glomerulus [7].
• This resistance is localized at the postsynaptic membrane containing more AChR-anchoring proteins, including S-laminin and rapsyn in aged animals [10].

Analytical, diagnostic and therapeutic context of Lamb2

• Finally, because the Lams gene mapped near two mutations that affect neuromuscular function, ducky (du) and tippy (tip), we assayed S-laminin by Southern blotting, immunoblotting, and immunohistochemistry in these mutants [7].

References