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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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 4

An insertion/deletion polymorphism in Ltbp4 predicts the phenotype in muscular dystrophy.

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An insertion/deletion polymorphism in Ltbp4 predicts the phenotype in mu...
Ltbp4 encodes a TGF-β–binding protein expressed in skeletal and cardiac muscle. (A) The gene structure is shown for Ltbp4. Exons 11, 12, 13 (red bars) of Ltbp4 encode a proline-rich region. (B) 129-Sgcg mice, with a milder phenotype, have a 36-bp insertion that encodes an extended proline-rich region, while severely affected D2-Sgcg mice have a deletion of 36 bp. The insertion/deletion occurs wholly within exon 12. (C) Ltbp4+36 correlates with reduced membrane permeability and reduced fibrosis in F2-Sgcg mice. Congenic Sgcg-null mice in the C57BL/6J background or in the CD1 background have a mild phenotype comparable to that of 129-Sgcg mice (7), and these mice also have the protective insertion Ltbp4+36 allele. mdx mice, the model for DMD, in the C57BL/10 background, also have the protective Ltbp4+36 allele.