Latent TGF-β–binding protein 4 modifies muscular dystrophy in mice
Ahlke Heydemann, … , Abraham A. Palmer, Elizabeth M. McNally
Ahlke Heydemann, … , Abraham A. Palmer, Elizabeth M. McNally
Published November 2, 2009
Citation Information: J Clin Invest. 2009;119(12):3703-3712. https://doi.org/10.1172/JCI39845.
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Research Article

Latent TGF-β–binding protein 4 modifies muscular dystrophy in mice

Abstract

Most single-gene diseases, including muscular dystrophy, display a nonuniform phenotype. Phenotypic variability arises, in part, due to the presence of genetic modifiers that enhance or suppress the disease process. We employed an unbiased mapping approach to search for genes that modify muscular dystrophy in mice. In a genome-wide scan, we identified a single strong locus on chromosome 7 that influenced two pathological features of muscular dystrophy, muscle membrane permeability and muscle fibrosis. Within this genomic interval, an insertion/deletion polymorphism of 36 bp in the coding region of the latent TGF-β–binding protein 4 gene (Ltbp4) was found. Ltbp4 encodes a latent TGF-β–binding protein that sequesters TGF-β and regulates its availability for binding to the TGF-β receptor. Insertion of 12 amino acids into the proline-rich region of LTBP4 reduced proteolytic cleavage and was associated with reduced TGF-β signaling, decreased fibrosis, and improved muscle pathology in a mouse model of muscular dystrophy. In contrast, a 12-amino-acid deletion in LTBP4 was associated with increased proteolysis, SMAD signaling, and fibrosis. These data identify Ltbp4 as a target gene to regulate TGF-β signaling and modify outcomes in muscular dystrophy.

Authors

Ahlke Heydemann, Ermelinda Ceco, Jackie E. Lim, Michele Hadhazy, Pearl Ryder, Jennifer L. Moran, David R. Beier, Abraham A. Palmer, Elizabeth M. McNally

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Figure 1

Mice lacking γ-sarcoglycan (Sgcg-null mice) serve as a model for muscular dystrophy.

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Mice lacking γ-sarcoglycan (Sgcg-null mice) serve as a model for muscula...
The Sgcg-null allele displays a mild phenotype in the 129 background strain (129-Sgcg) and a severe phenotype in the D2 strain (D2-Sgcg). Sgcg mice from the two backgrounds were interbred (F2-Sgcg), and the F2-Sgcg animals displayed an intermediate phenotype. (A) Muscle membrane leak in the quadriceps muscle was measured by Evans blue dye uptake in the 2 parental strains (129-Sgcg and D2-Sgcg) and the intercrossed F2-Sgcg generation. (B) Quadriceps muscle fibrosis was measured by determining HOP content in the two parental strains; the F2-Sgcg mice also revealed an intermediate phenotype. (C) An example of the phenotypic range is shown from diaphragm muscles from 2 F2-Sgcg animals (the two left panels) and 1 wild-type control (right panel). Dye uptake (blue) and fibrotic replacement (white) are shown. (D) Grip strength was measured in 8-week-old animals of the 129 and D2 backgrounds with and without the Sgcg-null allele. The D2-Sgcg mice were weaker than 129-Sgcg mice, while the parental strains without the muscular dystrophy gene were not significantly different.