Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome

Wei Lu, Carrie Phillips, Paul D. Killen, Tommy Hlaing, Wilbur R. Harrison, F. F B Elder, Jeffrey H. Miner, Paul A. Overbeek, Miriam H. Meisler

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Mice homozygous for the transgenic insertion in line OVE250 exhibit severe progressive glomerulonephritis. Ultrastructural changes in the glomerular basement membrane (GBM) at 2 weeks of age resemble those in Alport syndrome. The transgenic insertion site was mapped by FISH to mouse chromosome 1 close to Pax3. Genetic and molecular analyses identified a deletion of genomic DNA at the transgene insertion site. Exons 1 through 12 of the collagen IV gene Col4a4, exons 1 and 2 of the adjacent Col4a3 gene, and the intergenic promoter region are deleted. Transcripts of Col4a3 and Col4a4 are undetectable in mutant kidney, and both proteins are missing from the GBM. Persistent cellular proliferation in mutant kidneys suggests that interaction with the extracellular matrix may be important for cell maturation. Evolutionarily conserved sequence elements in the promoter regions of human and mouse Col4a3 and Col4a4 include a 19-bp element that was tandemly duplicated in the human lineage and a CTC box element common to several genes encoding extracellular matrix proteins. This new animal model of Alpoft syndrome, Col4Δ3-4, lacks both α3 and α4 chains of collagen IV and exhibits an earlier disease onset than mice lacking α3 only.

Original languageEnglish (US)
Pages (from-to)113-124
Number of pages12
JournalGenomics
Volume61
Issue number2
DOIs
StatePublished - Oct 15 1999
Externally publishedYes

Fingerprint

Hereditary Nephritis
Glomerular Basement Membrane
Collagen
Genetic Promoter Regions
Mutation
Exons
Genes
Kidney
Intergenic DNA
Conserved Sequence
Extracellular Matrix Proteins
Chromosomes, Human, Pair 1
Glomerulonephritis
Transgenes
Transgenic Mice
Extracellular Matrix
Molecular Biology
Animal Models
Cell Proliferation
DNA

ASJC Scopus subject areas

  • Genetics

Cite this

Lu, W., Phillips, C., Killen, P. D., Hlaing, T., Harrison, W. R., Elder, F. F. B., ... Meisler, M. H. (1999). Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome. Genomics, 61(2), 113-124. https://doi.org/10.1006/geno.1999.5943

Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome. / Lu, Wei; Phillips, Carrie; Killen, Paul D.; Hlaing, Tommy; Harrison, Wilbur R.; Elder, F. F B; Miner, Jeffrey H.; Overbeek, Paul A.; Meisler, Miriam H.

In: Genomics, Vol. 61, No. 2, 15.10.1999, p. 113-124.

Research output: Contribution to journalArticle

Lu, W, Phillips, C, Killen, PD, Hlaing, T, Harrison, WR, Elder, FFB, Miner, JH, Overbeek, PA & Meisler, MH 1999, 'Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome', Genomics, vol. 61, no. 2, pp. 113-124. https://doi.org/10.1006/geno.1999.5943
Lu, Wei ; Phillips, Carrie ; Killen, Paul D. ; Hlaing, Tommy ; Harrison, Wilbur R. ; Elder, F. F B ; Miner, Jeffrey H. ; Overbeek, Paul A. ; Meisler, Miriam H. / Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome. In: Genomics. 1999 ; Vol. 61, No. 2. pp. 113-124.
@article{e877d56cdebe4167a7ebb2fee5b8f0da,
title = "Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome",
abstract = "Mice homozygous for the transgenic insertion in line OVE250 exhibit severe progressive glomerulonephritis. Ultrastructural changes in the glomerular basement membrane (GBM) at 2 weeks of age resemble those in Alport syndrome. The transgenic insertion site was mapped by FISH to mouse chromosome 1 close to Pax3. Genetic and molecular analyses identified a deletion of genomic DNA at the transgene insertion site. Exons 1 through 12 of the collagen IV gene Col4a4, exons 1 and 2 of the adjacent Col4a3 gene, and the intergenic promoter region are deleted. Transcripts of Col4a3 and Col4a4 are undetectable in mutant kidney, and both proteins are missing from the GBM. Persistent cellular proliferation in mutant kidneys suggests that interaction with the extracellular matrix may be important for cell maturation. Evolutionarily conserved sequence elements in the promoter regions of human and mouse Col4a3 and Col4a4 include a 19-bp element that was tandemly duplicated in the human lineage and a CTC box element common to several genes encoding extracellular matrix proteins. This new animal model of Alpoft syndrome, Col4Δ3-4, lacks both α3 and α4 chains of collagen IV and exhibits an earlier disease onset than mice lacking α3 only.",
author = "Wei Lu and Carrie Phillips and Killen, {Paul D.} and Tommy Hlaing and Harrison, {Wilbur R.} and Elder, {F. F B} and Miner, {Jeffrey H.} and Overbeek, {Paul A.} and Meisler, {Miriam H.}",
year = "1999",
month = "10",
day = "15",
doi = "10.1006/geno.1999.5943",
language = "English (US)",
volume = "61",
pages = "113--124",
journal = "Genomics",
issn = "0888-7543",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome

AU - Lu, Wei

AU - Phillips, Carrie

AU - Killen, Paul D.

AU - Hlaing, Tommy

AU - Harrison, Wilbur R.

AU - Elder, F. F B

AU - Miner, Jeffrey H.

AU - Overbeek, Paul A.

AU - Meisler, Miriam H.

PY - 1999/10/15

Y1 - 1999/10/15

N2 - Mice homozygous for the transgenic insertion in line OVE250 exhibit severe progressive glomerulonephritis. Ultrastructural changes in the glomerular basement membrane (GBM) at 2 weeks of age resemble those in Alport syndrome. The transgenic insertion site was mapped by FISH to mouse chromosome 1 close to Pax3. Genetic and molecular analyses identified a deletion of genomic DNA at the transgene insertion site. Exons 1 through 12 of the collagen IV gene Col4a4, exons 1 and 2 of the adjacent Col4a3 gene, and the intergenic promoter region are deleted. Transcripts of Col4a3 and Col4a4 are undetectable in mutant kidney, and both proteins are missing from the GBM. Persistent cellular proliferation in mutant kidneys suggests that interaction with the extracellular matrix may be important for cell maturation. Evolutionarily conserved sequence elements in the promoter regions of human and mouse Col4a3 and Col4a4 include a 19-bp element that was tandemly duplicated in the human lineage and a CTC box element common to several genes encoding extracellular matrix proteins. This new animal model of Alpoft syndrome, Col4Δ3-4, lacks both α3 and α4 chains of collagen IV and exhibits an earlier disease onset than mice lacking α3 only.

AB - Mice homozygous for the transgenic insertion in line OVE250 exhibit severe progressive glomerulonephritis. Ultrastructural changes in the glomerular basement membrane (GBM) at 2 weeks of age resemble those in Alport syndrome. The transgenic insertion site was mapped by FISH to mouse chromosome 1 close to Pax3. Genetic and molecular analyses identified a deletion of genomic DNA at the transgene insertion site. Exons 1 through 12 of the collagen IV gene Col4a4, exons 1 and 2 of the adjacent Col4a3 gene, and the intergenic promoter region are deleted. Transcripts of Col4a3 and Col4a4 are undetectable in mutant kidney, and both proteins are missing from the GBM. Persistent cellular proliferation in mutant kidneys suggests that interaction with the extracellular matrix may be important for cell maturation. Evolutionarily conserved sequence elements in the promoter regions of human and mouse Col4a3 and Col4a4 include a 19-bp element that was tandemly duplicated in the human lineage and a CTC box element common to several genes encoding extracellular matrix proteins. This new animal model of Alpoft syndrome, Col4Δ3-4, lacks both α3 and α4 chains of collagen IV and exhibits an earlier disease onset than mice lacking α3 only.

UR - http://www.scopus.com/inward/record.url?scp=0033569491&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033569491&partnerID=8YFLogxK

U2 - 10.1006/geno.1999.5943

DO - 10.1006/geno.1999.5943

M3 - Article

VL - 61

SP - 113

EP - 124

JO - Genomics

JF - Genomics

SN - 0888-7543

IS - 2

ER -