title: Transgenic isolation of skeletal muscle and kidney defects in laminin beta2 mutant mice: implications for Pierson syndrome.
abstract: Pierson syndrome is a recently defined disease usually lethal within the first postnatal months and caused by mutations in the gene encoding laminin beta2 (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 beta2 either in muscle or in glomerular epithelial cells (podocytes) and crossed them onto the Lamb2(-/-) background. Rat beta2 was confined in skeletal muscle to synapses and myotendinous junctions, and in kidney to the glomerular basement membrane. In transgenic Lamb2(-/-) mice, beta2 deposition in only glomeruli prevented proteinuria but did not ameliorate the severe phenotype. By contrast, beta2 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.
authors.affiliation: Renal Division, Washington University School of Medicine, St Louis, MO 63110, USA. minerj@wustl.edu
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miner
authors.forename: Gloriosa
authors.initials: G
authors.lastname: Go
authors.forename: Jeanette
authors.initials: J
authors.lastname: Cunningham
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Patton
authors.forename: George
authors.initials: G
authors.lastname: Jarad
mesh_terms: D000818:Animals; D050533:Glomerular Basement Membrane / Q000002:abnormalities* / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D007797:Laminin / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000002:abnormalities* / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009469:Neuromuscular Junction / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D050199:Podocytes / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013569:Synapses / Q000737:chemistry / Q000378:metabolism; D013577:Syndrome
chemical_list: D007797:Laminin; C058783:laminin beta2