Transgenic Mouse Models of Marfan Syndrome (Fibrillin-1) Exhibit Elongated Ocular Axial Length

Abstract

Purpose: Marfan syndrome is an autosomal dominant genetic disorder attributed to mutations in the fibrillin-1 gene (FBN1). Ocular phenotypes associated with Marfan syndrome include elongated axial length, thinned sclera, high incidence of retinal detachment, and myopia. Although Marfan syndrome mouse models were developed in 1995, their ocular phenotype has not been characterized. This prospective study evaluated progression of axial length growth in 2 mouse models of Marfan syndrome using high-frequency ultrasound.

Methods: This study examined 9 age- and strain-matched mice of the C57BL/6J lineage: 6 males heterozygous for fibrillin-1 mutations, 3 B6.Cg-Fbn1^Tsk/J and 3 B6.129-Fbn1^tm1Hcd, as well as 3 wild-type control females. All mice were acquired from Jackson Laboratories (Bar Harbor, Maine, USA). High-frequency ultrasound (Quantel AVISO; Quantel Medical, Bozeman, Montana, USA) by a Lin50 50 MHz probe was used to acquire images of all eyes at 3 ages: 1.5 months, 2.5 months, and 5.5 months. Four ultrasound images were acquired for each eye, and measurements were made from the cornea (anteriorly) to the optic cup (posteriorly). Measurements were averaged for each eye at each age and were analyzed by the Wilcoxon Rank Sum Test. Limitations were signal attenuation by the large mouse lens and small sample size.

Results: Mean axial lengths of B6.Cg-Fbn1^Tsk/J and B6.129-Fbn1^tm1Hcd mice were significantly greater than that of their wild-type counterparts at 1.5 and 2.5 months of age (p = 0.0022, p = 0.0022). This finding became statistically insignificant at 5.5 months of age (p = 0.2406, p = 0.2406). Mean axial lengths of the 2 mouse models were similar at 1.5 months (p = 0.3939), greater in B6.Cg-Fbn1^Tsk/J as compared to the B6.129-Fbn1^tm1Hcd at 2.5 months (p = 0.0087), and trended toward greater in B6.129-Fbn1^tm1Hcd as compared to the B6.Cg-Fbn1^Tsk/J at 5.5 months (p = 0.0649).

Conclusions: Excessive axial length elongation occurs in humans with Marfan syndrome, and this study suggests that mouse models of this condition recapitulate the associated ocular phenotype. This pilot study may provide a foundational resource for understanding the ocular pathogenesis of Marfan syndrome as well as a potential platform for therapeutic intervention.

Keywords: 419 anatomy • 605 myopia • 539 genetics