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

Nature Genetics volume 27, pages 205–208 (2001)Cite this article

Abstract

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.

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Figure 1: Lmx1b expression in kidneys.
Figure 2: Extracellular matrix expression in Lmx1b−/− newborn mouse kidneys.
Figure 3: Immunohistochemical staining of type IV collagen chains.
Figure 4: COL4A3 and COL4A4 transcriptional regulation by LMX1B.

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Acknowledgements

We thank R.L. Johnson for Lmx1b−/− mice and O. Hernandez for editorial assistance. This work was supported by the Deutsche Forschungsgemeinschaft (S.D.D., B.Z.), the National Institutes of Health grants AR44738 (B.L.), DK53763 (P.S.T.), DK53196 (J.H.M.), and HD01204 (K.C.O.), March of Dimes Birth Defects Foundation (B.L.), the Arthritis Foundation (B.L., G.Z.), the Baylor College of Medicine Child Health Research Center (B.L.) and the Baylor College of Medicine Mental Retardation Research Center (B.L.).

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Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

    Roy Morello, Guang Zhou, Sandra D. Dreyer & Brendan Lee

  2. Department of Pediatrics, University of Mainz, Mainz, Germany

    Sandra D. Dreyer & Bernhard Zabel

  3. Division of Pathology, and Department of Pathobiology, Hospital for Sick Children, University of Toronto, Toronto, Canada

    Scott J. Harvey & Paul S. Thorner

  4. Department of Molecular Biology and Biochemistry, Okayama University Medical School, Okayama, Japan

    Yoshifumi Ninomiya

  5. Departments of Medicine (Renal Division), and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA

    Jeffrey H. Miner

  6. Division of Orthopedics, Hospital for Sick Children, Toronto, Canada

    William Cole

  7. Institute of Human Genetics, University of Hamburg, Hamburg, Germany

    Andreas Winterpacht

  8. Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, California, USA

    Kerby C. Oberg

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Correspondence to Brendan Lee.

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Morello, R., Zhou, G., Dreyer, S. et al. Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome. Nat Genet 27, 205–208 (2001). https://doi.org/10.1038/84853

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