Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome

Basement membrane (BM) morphogenesis is critical for normal kidney function1. Heterotrimeric type IV collagen, composed of different combinations of six α-chains (1-6), is a major matrix component of all BMs (ref. 2). Unlike in other BMs, glomerular BM (GBM) contains primarily the α3(IV) and α4(IV) chains, together with the α5(IV) chain3,4. A poorly understood, coordinated temporal and spatial switch in gene expression from ubiquitously expressed α1(IV) and α2(IV) collagen to the α3(IV), α4(IV) and α5(IV) chains occurs during normal embryogenesis of GBM (ref. 4). Structural abnormalities of type IV collagen have been associated with diverse biological processes including defects in molecular filtration in Alport syndrome5,6, cell differentiation in hereditary leiomyomatosis7, and autoimmunity in Goodpasture syndrome7; however, the transcriptional and developmental regulation of type IV collagen expression is unknown. Nail patella syndrome (NPS) is caused by mutations in LMX1B, encoding a LIM homeodomain transcription factor. Some patients have nephrosis-associated renal disease characterized by typical ultrastructural abnormalities of GBM (refs. 8,9). In Lmx1b^-/- mice, expression of both α(3)IV and α(4)IV collagen is strongly diminished in GBM, whereas that of α1, α2 and α5(IV) collagen is unchanged. Moreover, LMX1B binds specifically to a putative enhancer sequence in intron 1 of both mouse and human COL4A4 and upregulates reporter constructs containing this enhancer-like sequence. These data indicate that LMX1B directly regulates the coordinated expression of α3(IV) and α4(IV) collagen required for normal GBM morphogenesis and that its dysregulation in GBM contributes to the renal pathology and nephrosis in NPS.