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First published online 1 February 2006
doi: 10.1242/dev.02270

Development 133, 967-975 (2006)
Published by The Company of Biologists 2006
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Transgenic isolation of skeletal muscle and kidney defects in laminin ß2 mutant mice: implications for Pierson syndrome

Jeffrey H. Miner1,2,*, Gloriosa Go1, Jeanette Cunningham1, Bruce L. Patton3 and George Jarad1

1 Renal Division, Washington University School of Medicine, St Louis, MO 63110, USA.
2 Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO 63110, USA.
3 CROET, Oregon Health Sciences University, Portland, OR 97239, USA.

* Author for correspondence (e-mail: minerj{at}wustl.edu)

Accepted 3 January 2006

Pierson syndrome is a recently defined disease usually lethal within the first postnatal months and caused by mutations in the gene encoding laminin ß2 (LAMB2). The hallmarks of Pierson syndrome are congenital nephrotic syndrome accompanied by ocular abnormalities, including microcoria (small pupils), with muscular and neurological developmental defects also present. 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. 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. To investigate this, we generated transgenic mouse lines expressing rat laminin ß2 either in muscle or in glomerular epithelial cells (podocytes) and crossed them onto the Lamb2-/- background. Rat ß2 was confined in skeletal muscle to synapses and myotendinous junctions, and in kidney to the glomerular basement membrane. In transgenic Lamb2-/- mice, ß2 deposition in only glomeruli prevented proteinuria but did not ameliorate the severe phenotype. By contrast, ß2 expression in only muscle restored synaptic architecture and led to greatly improved health, but the mice died from kidney disease at 1 month. Rescue of both glomeruli and synapses was associated with normal weight gain, fertility and lifespan. 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.

Key words: Pierson syndrome, Human, LAMB2, Mouse, Rat




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