Modifier genes and their effect on Duchenne muscular dystrophy.
OBJECTIVE
Recently, genetic pathways that modify the clinical severity of Duchenne muscular dystrophy (DMD) have been identified. The pathways uncovered as modifiers are useful to predict prognosis and also elucidate molecular signatures that can be manipulated therapeutically.


RESULTS
Modifiers have been identified using combinations of transcriptome and genome profiling. Osteopontin, encoded by the SPP1 gene, was found using gene expression profiling. Latent TGFβ binding protein 4, encoding latent TGFβ binding protein 4 was initially discovered using a genome-wide screen in mice and then validated in cohorts of DMD patients. These two pathways converge in that they both regulate TGFβ. A third modifier, Anxa6 that specifies annexin A6, is a calcium binding protein that has been identified using mouse models, and regulates the injury pathway and sarcolemmal resealing.


CONCLUSIONS
Genetic modifiers can serve as biomarkers for outcomes in DMD. Modifiers can alter strength and ambulation in muscular dystrophy, and these same features can be used as endpoints used in clinical trials. Moreover, because genetic modifiers can influence outcomes, these genetic markers should be considered when stratifying results in muscular dystrophy.
Committee on Development, Regeneration and Stem Cell Biology, Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, The University of Chicago, Chicago, Illinois, USA.
Andy H
AH
Vo
Elizabeth M
EM
McNally
D000818:Animals; D017317:Annexin A6 / Q000235:genetics*; D060045:Genes, Modifier / Q000235:genetics*; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics*; D053495:Osteopontin / Q000235:genetics*
D017317:Annexin A6; C509040:LTBP4 protein, human; D053779:Latent TGF-beta Binding Proteins; C506895:SPP1 protein, human; D053495:Osteopontin