Replication of the WMS mutation in mice.

(a) The targeted Fbn1 locus. A neomycin selection cassette (PGK-Neo, flanked by FRT sites) was placed in the intron between exons 10 and 11. In addition, loxP sites were introduced before exons 10 and 11 and after exon 12. The neomycin cassette was removed by breeding targeted mice to FLPe mice. Cre-mediated recombination of the loxP sites resulted in deletion of exons 10–12, replicating the human WMS mutation. (b) Aortic root morphology. In contrast to Marfan mice, the aortic roots of 10 month old mutant mice showed no signs of fragmentation of the elastic lamellae. Scale bar = 25 µm. (c) Length measurements of long bones. μCT measurements revealed a reduction of 6–10% at 1 month of age, when homozygous mice were compared to gender-matched wildtype littermates (each bar represents the mean and standard deviation of measurements from 4 animals, n = 4). Significant p-values were obtained for all bones when comparisons were between homozygous and wildtype littermates. (d) Length measurements of skeletal elements in forepaws and hindpaws showed reduced digit length of metacarpals and proximal phalanges in WMΔ mutant mice relative to wildtype mice. All analyzed animals were gender matched littermates at 1 month of age (n = 5 for each genotype).