Maternal environment interacts with modifier genes to influence progression of nephrotic syndrome.
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.
Ratelade
Julien
J
INSERM, U574, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France.
Lavin
Tiphaine Aguirre
TA
Muda
Andrea Onetti
AO
Morisset
Ludivine
L
Mollet
Géraldine
G
Boyer
Olivia
O
Chen
Deborah S
DS
Henger
Anna
A
Kretzler
Matthias
M
Hubner
Norbert
N
Théry
Clotilde
C
Gubler
Marie-Claire
MC
Montagutelli
Xavier
X
Antignac
Corinne
C
Esquivel
Ernie L
EL
D000818:Animals; D018450:Disease Progression; D004777:Environment; D005260:Female; D023281:Genomics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007668:Kidney / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009404:Nephrotic Syndrome / Q000235:genetics* / Q000473:pathology; D010641:Phenotype
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein