title: LTBP4 genotype predicts age of ambulatory loss in Duchenne muscular dystrophy.
abstract: 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.
  
  
  CONCLUSIONS
  LTBP4 haplotype influences age at loss of ambulation, and should be considered in the management of DMD patients.
authors: Center for Gene Therapy, Nationwide Children' Hospital, Columbus, OH; Department of Pediatrics, Ohio State University, Columbus, OH; Department of Neurology, Ohio State University, Columbus, OH.
authors: Kevin M
authors: KM
authors: Flanigan
authors: Ermelinda
authors: E
authors: Ceco
authors: Kay-Marie
authors: KM
authors: Lamar
authors: Yuuki
authors: Y
authors: Kaminoh
authors: Diane M
authors: DM
authors: Dunn
authors: Jerry R
authors: JR
authors: Mendell
authors: Wendy M
authors: WM
authors: King
authors: Alan
authors: A
authors: Pestronk
authors: Julaine M
authors: JM
authors: Florence
authors: Katherine D
authors: KD
authors: Mathews
authors: Richard S
authors: RS
authors: Finkel
authors: Kathryn J
authors: KJ
authors: Swoboda
authors: Eduard
authors: E
authors: Gappmaier
authors: Michael T
authors: MT
authors: Howard
authors: John W
authors: JW
authors: Day
authors: Craig
authors: C
authors: McDonald
authors: Elizabeth M
authors: EM
authors: McNally
authors: Robert B
authors: RB
authors: Weiss
mesh_terms: D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics*; D008297:Male; D051346:Mobility Limitation; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D005938:Glucocorticoids; C509040:LTBP4 protein, human; D053779:Latent TGF-beta Binding Proteins; D051785:Smad Proteins