Received November 30, 2007
Accepted on February 26, 2008

BASIC RESEARCH

Maternal Environment Interacts with Modifier Genes to Influence Progression of Nephrotic Syndrome

Julien Ratelade ^*, Tiphaine Aguirre Lavin ^*, Andrea Onetti Muda ^*, Ludivine Morisset ^*, Géraldine Mollet ^*, Olivia Boyer ^*, Deborah S. Chen ^*, Anna Henger ^||, Matthias Kretzler ^||, Norbert Hubner ^¶, Clotilde Théry ^**, Marie-Claire Gubler ^*, Xavier Montagutelli , Corinne Antignac ^*, and Ernie L. Esquivel ^*1

*INSERM, U574, Hôpital Necker-Enfants Malades, Université Paris Descartes, Faculté de Médecine René Descartes, Departments of Pediatric Nephrology and Genetics, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, **INSERM, U653, Institut Curie, and Unité de Génétique des Mammifères, Institut Pasteur, Paris, France; Department of Pathology, Campus Biomedico University, Rome, Italy; ||Section of Nephrology, University of Michigan School of Medicine, Ann Arbor, Michigan; and ¶Max-Delbruck-Center for Molecular Medicine, Berlin-Buch, Germany

¹ To whom correspondence should be addressed. E-mail: esquivel{at}necker.fr.

	Abstract

Mutations in the NPHS2 gene, which encodes podocin, are responsible for some cases of sporadic and familial autosomal recessive steroid-resistant nephrotic syndrome. Inter- and intrafamilial variability in the progression of renal disease among patients bearing NPHS2 mutations suggests a potential role for modifier genes. Using a mouse model in which the podocin gene is constitutively inactivated, we sought to identify genetic determinants of the development and progression of renal disease as a result of the nephrotic syndrome. We report that the evolution of renal disease as a result of nephrotic syndrome in Nphs2-null mice depends on genetic background. Furthermore, the maternal environment significantly interacts with genetic determinants to modify survival and progression of renal disease. Quantitative trait locus mapping suggested that these genetic determinants may be encoded for by genes on the distal end of chromosome 3, which are linked to proteinuria, and on the distal end of chromosome 7, which are linked to a composite trait of urea, creatinine, and potassium. These loci demonstrate epistatic interactions with other chromosomal regions, highlighting the complex genetics of renal disease progression. In summary, constitutive inactivation of podocin models the complex interactions between maternal and genetically determined factors on the progression of renal disease as a result of nephrotic syndrome in mice.