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The nail-patella syndrome (NPS) is a rare autosomal-dominant disorder which is caused by loss-of-function mutations in the transcription factor LMX1B. NPS is characterized by dysplastic nails, absent or hypoplastic patellae, minor skeletal abnormalities and nephropathy (in 20–40% of the cases), which is the most severe aspect of the disorder. The current data suggest that genetic modifiers in the outbred human genetic background are responsible for this variable phenotype. Preliminary work on the function of Lmx1b in the kidney has been performed using Lmx1b knockout mice (Lmx1b−/−). Although Lmx1b−/− mice die within 24 h after birth, they exhibit the characteristic NPS features including the renal abnormalities. But in contrast to the situation in human, no phenotype could so far be detected in heterozygous Lmx1b+/− mice. This indicates that our understanding of the pathomechanism underlying the nephropathy is still very limited. In an attempt to further evaluate these mechanisms, we tried to induce a renal phenotype in Lmx1b+/− mice, and thus model the human (NPS) situation. We applied unilateral nephrectomy as a model to induce nephron loss and detected a significant (p = 0.02) reduction in compensatory renal growth in heterozygous knockout animals (Lmx1b+/−) compared to Lmx1b+/+ animals, which was correlated with a significantly lower increase in glomerular volume (VG) (p = 0.0034) and an increase in glomerulosclerosis (p = 0.085). Thus, Lmx1b deficiency in heterozygous Lmx1b (Lmx1b+/−) knockout mice profoundly affects the compensatory response to nephron loss. Moreover, this is the first report of a phenotype in heterozygous Lmx1b (Lmx1b+/−) knockout animals.