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Dominant mutations of Col4a1 result in basement membrane defects which lead to anterior segment dysgenesis and glomerulopathy
- Source :
- Human molecular genetics. 14(21)
- Publication Year :
- 2005
-
Abstract
- Members of the type IV collagen family are essential components of all basement membranes (BMs) and define structural stability as well as tissue-specific functions. The major isoform, alpha1.alpha1.alpha2(IV), contributes to the formation of many BMs and its deficiency causes embryonic lethality in mouse. We have identified an allelic series of three ENU induced dominant mouse mutants with missense mutations in the gene Col4a1 encoding the alpha1(IV) subunit chain. Two severe alleles (Bru and Svc) have mutations affecting the conserved glycine residues in the Gly-Xaa-Yaa collagen repeat. Bru heterozygous mice display defects similar to Axenfeld-Rieger anomaly, including iris defects, corneal opacity, vacuolar cataracts, significant iris/corneal adhesions, buphthalmos and optic nerve cupping, a sign indicative of glaucoma. Kidneys of Bru mice have peripheral glomerulopathy characterized by hypertrophy and hyperplasia of the parietal epithelium of Bowman's capsule. A milder allele (Raw) contains a mutation in the Yaa residue of the collagen repeat and was identified by a silvery appearance of the retinal arterioles. All phenotypes are associated with BM defects that affect the eye, kidney and other tissues. This allelic series shows that mutations affecting the collagen domain cause dominant negative effects on the expression and function of the major collagen IV isoform alpha1(IV), and pathological effects vary with the individual mutations.
- Subjects :
- Gene isoform
Collagen Type IV
Eye Diseases
Molecular Sequence Data
Mutation, Missense
Biology
medicine.disease_cause
Glomerulonephritis, Membranous
Type IV collagen
Mice
Microscopy, Electron, Transmission
Glomerulopathy
Glomerular Basement Membrane
Genetics
medicine
Missense mutation
Animals
Abnormalities, Multiple
Amino Acid Sequence
Allele
Molecular Biology
Genetics (clinical)
Genes, Dominant
Basement membrane
Mutation
Base Sequence
General Medicine
Sequence Analysis, DNA
medicine.disease
Molecular biology
Immunohistochemistry
eye diseases
Buphthalmos
medicine.anatomical_structure
Electrophoresis, Polyacrylamide Gel
sense organs
Microsatellite Repeats
Subjects
Details
- ISSN :
- 09646906
- Volume :
- 14
- Issue :
- 21
- Database :
- OpenAIRE
- Journal :
- Human molecular genetics
- Accession number :
- edsair.doi.dedup.....ae8a9652e8f0d62428a26e87553aecc2