<i><scp>LTBP4</scp></i> genotype predicts age of ambulatory loss in duchenne muscular dystrophy

<jats:sec><jats:title>Objective</jats:title><jats:p>Duchenne muscular dystrophy (DMD) displays a clinical range that is not fully explained by the primary <jats:italic>DMD</jats:italic> mutations. <jats:italic>Ltbp4</jats:italic>, 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 <jats:italic>LTBP4</jats:italic> genotype influenced DMD severity in a large patient cohort.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We analyzed nonsynonymous single nucleotide polymorphisms (SNPs) from human <jats:italic>LTBP4</jats:italic> in 254 nonambulatory subjects with known <jats:italic>DMD</jats:italic> mutations. These SNPs, V194I, T787A, T820A, and T1140M, form the VTTT and IAAM <jats:italic>LTBP4</jats:italic> haplotypes.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Individuals homozygous for the IAAM <jats:italic>LTBP4</jats:italic> 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.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p><jats:italic>LTBP4</jats:italic> haplotype influences age at loss of ambulation, and should be considered in the management of DMD patients. ANN NEUROL 2013;73:481–488</jats:p></jats:sec>