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doi:10.1534/genetics.106.064733
A more recent version of this article appeared on February 1, 2007.
REGULAR RESEARCH PAPERS |
Type IV procollagen missense mutations associated with defects of the eye, vascular stability, 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 2 Col4a2 mutant alleles
Jack Favor 1*, Christian Johannes Gloeckner 1, Dirk Janik 2, Martina Klempt 2, Angelika Neuhäuser-Klaus 1, Walter Pretsch 1, Wolfgang Schmahl 2 and Leticia Quintanilla-Fend 3
1 GSF-Res. Center for Environment and Health, Institute of Human Genetics
2 Ludwig-Maximilians-University
3 GSF-Res. Center for Environment and Health, Institute of Pathology
* To whom correspondence should be addressed. E-mail: favor{at}gsf.de.
Submitted on August 11, 2006
Revised on August 30, 2006
Accepted on 28 November 2006
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[((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, brain, kidney function, vascular stability and viability. Homozygotes do not survive beyond the second trimester. Ten mutations result in amino acid substitutions at conserved Gly sites within the collagenous domain, one mutation is in the carboxy-terminal non-collagenous 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 intra-orbital hemorrhages observed in the mouse to be a clinically relevant phenotype with a relatively high predictive value to identify carriers of COL4A1 or COL4A2 mutations.
Key Words: basement membrane, dysmorphology, missense mutations, type IV collagen
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