Type IV Procollagen Missense Mutations Associated With Defects of the Eye, Vascular Stability, the Brain, Kidney Function and Embryonic or Postnatal Viability in the Mouse, Mus musculus: An Extension of the Col4a1 Allelic Series and the Identification of the First Two Col4a2 Mutant Alleles
- 1 February 2007
- journal article
- Published by Oxford University Press (OUP) in Genetics
- Vol. 175 (2), 725-736
- https://doi.org/10.1534/genetics.106.064733
Abstract
The basement membrane is important for proper tissue development, stability, and physiology. Major components of the basement membrane include laminins and type IV collagens. The type IV procollagens Col4a1 and Col4a2 form the heterotrimer [α1(IV)]2[α2(IV)], which is ubiquitously expressed in basement membranes during early developmental stages. We present the genetic, molecular, and phenotypic characterization of nine Col4a1 and three Col4a2 missense mutations recovered in random mutagenesis experiments in the mouse. Heterozygous carriers express defects in the eye, the brain, kidney function, vascular stability, and viability. Homozygotes do not survive beyond the second trimester. Ten mutations result in amino acid substitutions at nine conserved Gly sites within the collagenous domain, one mutation is in the carboxy-terminal noncollagenous domain, and one mutation is in the signal peptide sequence and is predicted to disrupt the signal peptide cleavage site. Patients with COL4A2 mutations have still not been identified. We suggest that the spontaneous intraorbital hemorrhages observed in the mouse are a clinically relevant phenotype with a relatively high predictive value to identify carriers of COL4A1 or COL4A2 mutations.Keywords
This publication has 74 references indexed in Scilit:
- Neonatal porencephaly and adult stroke related to mutations in collagen IV A1Annals of Neurology, 2006
- Improved Prediction of Signal Peptides: SignalP 3.0Journal of Molecular Biology, 2004
- Reelin signaling directly affects radial glia morphology and biochemical maturationDevelopment, 2003
- Expression and adhesive properties of basement membrane proteins in cerebral capillary endothelial cell culturesCell and tissue research, 2002
- Basement Membrane Type IV Collagen Molecules in the Choroid Plexus, Pia Mater and Capillaries in the Mouse Brain.Archives of Histology and Cytology, 2002
- Insertional Mutation of the Collagen Genes Col4a3 and Col4a4 in a Mouse Model of Alport SyndromeGenomics, 1999
- Essential role of α6 integrins in cortical and retinal laminationCurrent Biology, 1998
- Molecular and functional defects in kidneys of mice lacking collagen alpha 3(IV): implications for Alport syndrome.The Journal of cell biology, 1996
- Collagen IV alpha 3, alpha 4, and alpha 5 chains in rodent basal laminae: sequence, distribution, association with laminins, and developmental switches.The Journal of cell biology, 1994
- Dominant cataract and recessive specific-locus mutations detected in offspring of procarbazine-treated male miceMutation research. Reviews in mutation research, 1988