COL4A4
Collagen alpha-4(IV) chain precursor
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A heterozygous mutation in autosomal Alport genes COL4A3 and COL4A4 can be found in 20 to 50% of individuals with familial benign hematuria and diffuse glomerular basement membrane thinning (thin basement membrane nephropathy [TBMN]). Approximately 1% of humans are heterozygous carriers of mutations in the autosomal Alport genes and at risk for developing renal failure as a result of TBMN. The incidence and pathogenesis of renal failure in heterozygous COL4A3/4 mutation carriers is still unclear and was examined further in this study using COL4A3 knockout mice. In heterozygous COL4A3( /-) mice lifespan, hematuria and renal function (serum urea and proteinuria) were monitored during a period of 3 yr, and renal tissue was examined by light and electron microscopy, immunohistochemistry, and Western blot. Lifespan of COL4A3( /-) mice was found to be significantly shorter than in healthy controls (21.7 versus 30.3 mo). Persistent glomerular hematuria was detected starting in week 9; proteinuria of > 0.1 g/L started after 3 mo of life and increased to > 3 g/L after 24 mo. The glomerular basement membrane was significantly thinned (167 versus 200 nm in wild type) in 30-wk-old mice, coinciding with focal glomerulosclerosis, tubulointerstitial fibrosis, and increased levels of TGF-beta and connective tissue growth factor. The renal phenotype in COL4A3( /-) mice resembled the clinical and histopathologic phenotype of human cases of TBMN with concomitant progression to chronic renal failure. Therefore, the COL4A3( /-) mouse model will help in the understanding of the pathogenesis of TBMN in humans and in the evaluation of potential therapies.
MeSH Terms
- Aging
- Animals
- Collagen Type IV
- Disease Models, Animal
- Extracellular Matrix
- Glomerular Basement Membrane
- Glomerulonephritis, Membranous
- Kidney
- Kidney Failure, Chronic
- Longevity
- Mice
- Mice, Transgenic
- Nephritis, Hereditary
- Phenotype
- Transforming Growth Factor beta
- Transforming Growth Factor beta1
Little is known about mechanisms regulating gene expression for the alpha chains of basement membrane type IV collagen, arranged head-to-head in transcription units COL4A1-COL4A2, COL4A3-COL4A4, and COL4A5-COL4A6, and implicated broadly in genetic diseases. To investigate these mechanisms, we generated transgenic mouse lines bearing 5'-flanking sequences of COL4A5 and COL4A6, cloned upstream of a lacZ reporter gene. A 3.8-kb fragment upstream of COL4A6 directs reporter gene expression in the esophagus, stomach, and duodenum, whereas a 13.8-kb fragment directs expression in the esophagus only. A 10.6-kb fragment upstream of COL4A5 directs expression in the esophagus. Coupled with evidence of long-range conservation between human and mouse non-coding sequences, described herein, our findings provide the first indication that highly specialized patterns characteristic of COL4A5-COL4A6 expression in vivo arise from effects of distributed cis-acting regulatory elements on a bidirectional proximal promoter, itself transcriptionally competent.
MeSH Terms
- Aging
- Amino Acid Sequence
- Animals
- Collagen Type IV
- Gene Expression Regulation
- Genes, Regulator
- Humans
- Mice
- Mice, Transgenic
- Molecular Sequence Data
- Organ Specificity
- Protein Subunits
- Sequence Homology
- Species Specificity
- Tissue Distribution
- Transcriptional Activation
- Upper Gastrointestinal Tract