title: Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome.
abstract: Basement membrane (BM) morphogenesis is critical for normal kidney function. Heterotrimeric type IV collagen, composed of different combinations of six alpha-chains (1-6), is a major matrix component of all BMs (ref. 2). Unlike in other BMs, glomerular BM (GBM) contains primarily the alpha 3(IV) and alpha 4(IV) chains, together with the alpha 5(IV) chain. A poorly understood, coordinated temporal and spatial switch in gene expression from ubiquitously expressed alpha 1(IV) and alpha 2(IV) collagen to the alpha 3(IV), alpha 4(IV) and alpha 5(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 syndrome, cell differentiation in hereditary leiomyomatosis, and autoimmunity in Goodpasture syndrome; 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 alpha(3)IV and alpha(4)IV collagen is strongly diminished in GBM, 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 alpha 3(IV) and alpha 4(IV) collagen required for normal GBM morphogenesis and that its dysregulation in GBM contributes to the renal pathology and nephrosis in NPS.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: R
authors.initials: R
authors.lastname: Morello
authors.forename: G
authors.initials: G
authors.lastname: Zhou
authors.forename: S D
authors.initials: SD
authors.lastname: Dreyer
authors.forename: S J
authors.initials: SJ
authors.lastname: Harvey
authors.forename: Y
authors.initials: Y
authors.lastname: Ninomiya
authors.forename: P S
authors.initials: PS
authors.lastname: Thorner
authors.forename: J H
authors.initials: JH
authors.lastname: Miner
authors.forename: W
authors.initials: W
authors.lastname: Cole
authors.forename: A
authors.initials: A
authors.lastname: Winterpacht
authors.forename: B
authors.initials: B
authors.lastname: Zabel
authors.forename: K C
authors.initials: KC
authors.lastname: Oberg
authors.forename: B
authors.initials: B
authors.lastname: Lee
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism*; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics*; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009261:Nail-Patella Syndrome / Q000150:complications*; D051437:Renal Insufficiency / Q000209:etiology*; D014157:Transcription Factors; D014158:Transcription, Genetic
chemical_list: D018398:Homeodomain Proteins; C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D003094:Collagen