Originally published as Genetics Published Articles Ahead of Print on December 18, 2006.

Genetics, Vol. 175, 725-736, February 2007, Copyright © 2007
doi:10.1534/genetics.106.064733

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

Jack Favor^*,1, Christian Johannes Gloeckner^*, Dirk Janik, Martina Klempt, Angelika Neuhäuser-Klaus^*, Walter Pretsch^*, Wolfgang Schmahl and Leticia Quintanilla-Fend

^* Institute of Human Genetics and Institute of Pathology, GSF—National Research Center for Environment and Health, D-85764 Neuherberg, Germany and Chair of General Pathology and Neuropathology and Institute of Molecular Animal Breeding and Biotechnology, Veterinary Faculty, Ludwig-Maximilians-University, D-80539 Munich, Germany

¹ Corresponding author: Institute of Human Genetics, GSF—National Research Center for Environment and Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany. 
E-mail: favor{at}gsf.de

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 [1(IV)]₂[2(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.

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