Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome
J. Clin. Invest. Daniel P. Judge, et al. 114:172 doi:10.1172/JCI20641 [Go to this article.]

Figure 6
(A) Cysteine substitution in fibrillin-1 results in impaired microfibril formation. Cultured dermal fibroblasts from WT, heterozygous (C1039G/+), or homozygous (C1039G/C1039G) mice (for the Fbn1 mutation) were plated at 5 × 10⁵/ml and immunostained for fibrillin-1 using polyclonal anti–fibrillin-1 Ab 9543 after 72 hours of confluence. The quantity and quality of the microfibrils containing the product of the mutant allele appears diminished. (B) Representative aortic wall sections from mice aged 6 months, stained with H&E (left) and Safranin-O (right). Top panels are from a WT control, and bottom panels are from a mouse heterozygous for the C1039G mutation (C1039G/+). Mutant mice have focal areas of medial thickening with disorganization and disruption of elastic lamellae, as well as frequent areas of proteoglycan deposition (arrow). Magnification, ×40 for all sections. Scale bar: 25 μm. (C) Representative aortic wall sections from mice heterozygous for the C1039G mutation and harboring the WT FBN1 transgene, +Tg(WT), or the C1663R-mutant FBN1 transgene, +Tg(mut3). Aortic wall organization is greatly improved by the WT transgene and partly improved by the mutant transgene. Magnification, ×40 for all sections. Scale bar: 25 μm. (D) Average aortic wall thickness (μm) from at least five mice of each genotype at age 6 months. For each mouse, at least six independent sections were examined, and for each section, four measures of the aortic wall thickness were averaged, including the thickest and thinnest, for each section.