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). Unlik e in other BMs, glomerular BM (CBM) contains primarily the alpha3(IV) and a lpha4(IV) chains, together with the alpha5(IV) chain(3,4). A poorly underst ood, coordinated temporal and spatial switch in gene expression from ubiqui tously expressed alpha1(IV) and alpha2(IV) collagen to the alpha3(IV), alph a4(IV) and alpha5(IV) chains occurs during nqrmat embryogenesis of CBM (ref . 4). Structural abnormalities of type IV collagen have been associated wit h 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. Na il patella syndrome (NPS) is caused by mutations in LMX1B, encoding a LIM h omeodomain transcription factor. Some patients have nephrosis-associated re nal 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 an d upregulates reporter constructs containing this enhancer-like sequence. T hese data indicate that LMX1B directly regulates the coordinated expression of alpha3(IV) and alpha (IV) collagen required for normal CBM morphogenesi s and that its dysregulation in CBM contributes to the renal pathology and nephrosis in NPS.