Letting Nature Teach Us How to Cure Genetic Disease: The Identification of Modifier Genes
Jefferson J. Doyle; Alex J. Doyle; Robert D. Wardlow; Djahida Bedja; Harry C. Dietz
Johns Hopkins School of Medicine, Boston Children’s Hospital & Harvard Medical School
Baltimore, MD; Boston, MA
Introduction: Disorders caused by mutations in a single gene can show a range of disease severity, the cause of which is often unknown (1). We used a mouse model of Marfan syndrome (MFS) to identify modifier genes that represent novel therapeutic targets.
Methods: There are many inbred mouse strains, with distinct genetic compositions. We backcrossed MFS mice onto pure C57BL/6J (BL6) and 129S6 (129) strains and assessed systemic disease severity. We measured globe axial length (AL) in-vivo using interferometry. We bred intercrossed BL6/129-MFS mice to map modifier genes, and generated 129-MFS mice null for two candidate modifier genes.
Results: Compared to BL6-MFS mice, 129-MFS animals had greater aortic root aneurysm (p<0.0001), premature death from aortic dissection (p=0.007), lung disease (p<0.01) and spine kyphosis (p<0.05). 129-MFS animals selectively showed greater AL than WT littermates (p=0.002). We identified 2 QTLs on chromosomes 5 and 11 that linked with disease severity (p=0.008). We used the mouse genome project to identify Mmp17 (chromosome 5) and Map2k6 (chromosome 11) as likely modifier genes, knockout of which completely prevented severe disease in 129-MFS mice.
Discussion: This work identified two genes that strongly modulate disease severity in MFS mice. Parallel work in MFS patients identified MAP3K4 as a likely modifier gene; this is a direct activator of MAP2K6, establishing a common pathway of genetic modification in MFS that is shared between mice and humans.
Conclusion: We have identified two novel therapeutic targets to treat MFS, and are exploring small molecule inhibitors of these proteins to treat its ocular and non-ocular manifestations.
References: 1. De Backer J, Loeys B, Leroy B, Coucke P, Dietz H, De Paepe A. Utility of molecular analyses in the exploration of extreme intrafamilial variability in the Marfan syndrome. Clin Genet 2007:72(3);188-98.