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

doi:10.1002/ana.23819

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LTBP4 genotype predicts age of ambulatory loss in duchenne muscular dystrophy

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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, …

Annals of neurology, Vol.73(4), pp.481-488

04/2013

DOI: 10.1002/ana.23819

PMCID: PMC4106425

PMID: 23440719

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https://www.ncbi.nlm.nih.gov/pmc/articles/4106425View

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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. Interpretation LTBP4 haplotype influences age at loss of ambulation, and should be considered in the management of DMD patients. ANN NEUROL 2013;73:481–488

Details

Title: Subtitle: LTBP4 genotype predicts age of ambulatory loss in duchenne muscular dystrophy
Creators: Kevin M Flanigan - Ohio State University
Ermelinda Ceco - University of Chicago
Kay‐Marie Lamar - University of Chicago
Yuuki Kaminoh - Nationwide Children' Hospital
Diane M Dunn - University of Utah School of Medicine
Jerry R Mendell - Ohio State University
Wendy M King - Ohio State University
Alan Pestronk - Washington University at St Louis
Julaine M Florence - Washington University at St Louis
Katherine D Mathews - University of Iowa Carver College of Medicine
Richard S Finkel - University of Pennsylvania
Kathryn J Swoboda - University of Utah School of Medicine
Eduard Gappmaier - University of Utah
Michael T Howard - University of Utah School of Medicine
John W Day - University of Minnesota
Craig McDonald - University of California
Elizabeth M McNally - University of Chicago
Robert B Weiss - University of Utah School of Medicine
Resource Type: Journal article
Publication Details: Annals of neurology, Vol.73(4), pp.481-488
DOI: 10.1002/ana.23819
PMID: 23440719
PMCID: PMC4106425
NLM abbreviation: Ann Neurol
ISSN: 0364-5134
eISSN: 1531-8249
Number of pages: 8
Language: English
Date published: 04/2013
Academic Unit: Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
Record Identifier: 9984014844202771

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