title: 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.
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 [alpha1(IV)]2[alpha2(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.
authors.affiliation: Institute of Human Genetics, GSF-National Research Center for Environment and Health, D-85764 Neuherberg, Germany. favor@gsf.de
authors.forename: Jack
authors.initials: J
authors.lastname: Favor
authors.forename: Christian Johannes
authors.initials: CJ
authors.lastname: Gloeckner
authors.forename: Dirk
authors.initials: D
authors.lastname: Janik
authors.forename: Martina
authors.initials: M
authors.lastname: Klempt
authors.forename: Angelika
authors.initials: A
authors.lastname: Neuhäuser-Klaus
authors.forename: Walter
authors.initials: W
authors.lastname: Pretsch
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schmahl
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Fend
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001808:Blood Vessels / Q000503:physiopathology*; D001921:Brain / Q000196:embryology / Q000503:physiopathology*; D002874:Chromosome Mapping; D020090:Chromosome Segregation; D024141:Collagen Type IV / Q000737:chemistry / Q000235:genetics*; D003433:Crosses, Genetic; D004622:Embryo, Mammalian / Q000002:abnormalities; D005123:Eye / Q000196:embryology / Q000473:pathology; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D005328:Fetal Viability / Q000235:genetics*; D006405:Hematology; D006579:Heterozygote; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D021382:Protein Sorting Signals; D014886:Weaning
chemical_list: D024141:Collagen Type IV; D050505:Mutant Proteins; D021382:Protein Sorting Signals