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(American Journal of Pathology. 2003;163:145-155.)
© 2003 American Society for Investigative Pathology

In Vivo Expression of Putative LMX1B Targets in Nail-Patella Syndrome Kidneys

Laurence Heidet^*, Ernie M. H. F. Bongers, Mireille Sich^*, Shao-Yu Zhang^*, Chantal Loirat, Alain Meyrier, Michel Broyer^¶, Gérard Landthaler^||, Bernadette Faller^**, Yoshikazu Sado, Nine V. A. M. Knoers and Marie-Claire Gubler^*

From INSERM U574^* and the Département de Néphrologie Pédiatrique,^¶ Université René Descartes, Hôpital Necker–Enfants Malades, Paris, France; the Service de Néphrologie, Hôpital Robert Debré, Paris, France; the Département de Néphrologie, Hôpital Européen Georges Pompidou, Paris, France; the Service de Pédiatrie,|| Hôpital Charles Nicolle, Rouen, France; the Service de Néphrologie,^** Hospices Civils, Colmar, France; the Department of Human Genetics, University Medical Centre, Nijmegen, The Netherlands; and the Division of Immunology, Shigei Medical Research Institute, Okayama, Japan

The nail-patella syndrome (NPS) is characterized by nail and bone abnormalities, associated with glomerular involvement in 40% of patients. Typical glomerular changes consist of fibrillar material in the irregularly thickened glomerular basement membrane. NPS is inherited as an autosomal dominant trait and caused by heterozygous loss of function mutations in LMX1B, a member of the LIM homeodomain protein family. Mice with homozygous inactivation of the gene exhibit nail and skeletal defects, similar to those observed in patients, associated with glomerular abnormalities. Strong reduction in the glomerular expression of the 3 and 4 chains of type IV collagen, and of podocin and CD2AP, two podocyte proteins critical for glomerular function, has been observed in Lmx1b null mice. The expression of these proteins appeared to be regulated by Lmx1b. To determine whether these changes in podocyte gene expression are involved in the development of NPS nephropathy, using immunohistological techniques, we analyzed the podocyte phenotype and the renal distribution of type IV collagen chains in the kidneys of seven NPS patients with severe glomerular disease. We also examined the nature of the fibrillar material present within the glomerular extracellular matrix. The glomerular basement membrane fibrillar material was specifically labeled with anti-type III collagen antibodies, suggesting a possible regulation of type III collagen expression by LMX1B. The expression of the 3 and 4 chains of type IV collagen, and of podocin and CD2AP, was found to be normal in the seven patients. These findings indicate that heterozygous mutations of LMX1B do not appear to dramatically affect the expression of type IV collagen chains, podocin, or CD2AP in NPS patients.

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