LTBP4 genotype predicts age of ambulatory loss in duchenne muscular dystrophy

Kevin M. Flanigan, Ermelinda Ceco, Kay Marie Lamar, Yuuki Kaminoh, Diane M. Dunn, Jerry R. Mendell, Wendy M. King, Alan Pestronk, Julaine M. Florence, Katherine D. Mathews, Richard S. Finkel, Kathryn J. Swoboda, Eduard Gappmaier, Michael T. Howard, John W. Day, Craig McDonald, Elizabeth M. McNally, Robert B. Weiss

Research output: Contribution to journalArticlepeer-review

149 Scopus citations


Objective: Duchenne muscular dystrophy (DMD) displays a clinical range that is not fully explained by the primary DMD mutations. Ltbp4, encoding latent transforming growth factor-β binding protein 4, was previously discovered in a genome-wide scan as a modifier of murine muscular dystrophy. We sought to determine whether LTBP4 genotype influenced DMD severity in a large patient cohort. Methods: We analyzed nonsynonymous single nucleotide polymorphisms (SNPs) from human LTBP4 in 254 nonambulatory subjects with known DMD mutations. These SNPs, V194I, T787A, T820A, and T1140M, form the VTTT and IAAM LTBP4 haplotypes. Results: Individuals homozygous for the IAAM LTBP4 haplotype remained ambulatory significantly longer than those heterozygous or homozygous for the VTTT haplotype. Glucocorticoid-treated patients who were IAAM homozygotes lost ambulation at 12.5 ± 3.3 years compared to 10.7 ± 2.1 years for treated VTTT heterozygotes or homozygotes. IAAM fibroblasts exposed to transforming growth factor (TGF) β displayed reduced phospho-SMAD signaling compared to VTTT fibroblasts, consistent with LTBP4' role as a regulator of TGFβ. Interpretation: LTBP4 haplotype influences age at loss of ambulation, and should be considered in the management of DMD patients.

Original languageEnglish
Pages (from-to)481-488
Number of pages8
JournalAnnals of neurology
Issue number4
StatePublished - Apr 2013


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