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 function(1). Heterotrimeric type IV collagen, composed of different combinations of six ct-chains lid), is a major matrix component of all BMs (ref. 2). Unlike in other BMs, glomerular BM (CBM) contains primarily the alpha3(IV) and alpha4(IV) chains, together with the alpha5(IV) chain(3,4). A poorly understood, coordinated temporal and spatial switch in gene expression from ubiquitously expressed alpha1(IV) and alpha2(IV) collagen to the alpha3(IV), alpha4(IV) and alpha5(IV) chains occurs during nqrmat embryogenesis of CBM (ref. 4). Structural abnormalities of type IV collagen have been associated with diverse biological processes including defects in molecular filtration in Alport syndrome(5,6), cell differentiation in hereditary leiomyomatosis(7), and autoimmunity in Goodpasture syndrome(7); 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 GEM (refs. 8,9). In Lmx1b(-/-) mice, expression of both alpha (3)IV and alpha (4)IV collagen is strongly diminished in GEM, whereas that of alpha1, alpha2 and alpha5(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 alpha3(IV) and alpha (IV) collagen required for normal CBM morphogenesis and that its dysregulation in CBM contributes to the renal pathology and nephrosis in NPS.