Leaders in Pharmaceutical Business Intelligence (LPBI) Group

1. Fedik Rahimov^a,^b,¹,

2. Oliver D. King^b,^c,¹,
3. Doris G. Leung^d,^e,
4. Genila M. Bibat^d,
5. Charles P. Emerson, Jr^b,^c,
6. Louis M. Kunkel^a,^b,^f,², and
7. Kathryn R. Wagner^d,^e,^g,²

+Author Affiliations

1. 
   
   ^aProgram in Genomics, Division of Genetics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115;
2. 
   
   ^bThe Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center and
3. 
   
   ^cBoston Biomedical Research Institute, Watertown, MA 02472;
4. 
   
   ^dHugo W. Moser Research Institute at Kennedy Krieger Institute, Baltimore, MD 21205; Departments of
5. 
   
   ^eNeurology and
6. 
   
   ^gNeuroscience, The Johns Hopkins School of Medicine, Baltimore, MD 21205; and
7. 
   
   ^fThe Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA 02115

1. Contributed by Louis M. Kunkel, June 4, 2012 (sent for review May 24, 2012)

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disorder caused by contractions of repetitive elements within the macrosatellite D4Z4 on chromosome 4q35. The pathophysiology of FSHD is unknown and, as a result, there is currently no effective treatment available for this disease. To better understand the pathophysiology of FSHD and develop mRNA-based biomarkers of affected muscles, we compared global analysis of gene expression in two distinct muscles obtained from a large number of FSHD subjects and their unaffected first-degree relatives. Gene expression in two muscle types was analyzed using GeneChip Gene 1.0 ST arrays: biceps, which typically shows an early and severe disease involvement; and deltoid, which is relatively uninvolved. For both muscle types, the expression differences were mild: using relaxed cutoffs for differential expression (fold change ≥1.2; nominal P value <0.01), we identified 191 and 110 genes differentially expressed between affected and control samples of biceps and deltoid muscle tissues, respectively, with 29 genes in common. Controlling for a false-discovery rate of <0.25 reduced the number of differentially expressed genes in biceps to 188 and in deltoid to 7. Expression levels of 15 genes altered in this study were used as a “molecular signature” in a validation study of an additional 26 subjects and predicted them as FSHD or control with 90% accuracy based on biceps and 80% accuracy based on deltoids.

Footnotes

• ↵¹F.R. and O.D.K. contributed equally to this work.

• ↵²To whom correspondence may be addressed. E-mail:kunkel@enders.tch.harvard.edu or wagnerk@kennedykrieger.org.

• Author contributions: F.R., O.D.K., C.P.E., L.M.K., and K.R.W. designed research; F.R., O.D.K., D.G.L., and G.M.B. performed research; D.G.L., G.M.B., and K.R.W. contributed new reagents/analytic tools; F.R., O.D.K., C.P.E., L.M.K., and K.R.W. analyzed data; and F.R., O.D.K., L.M.K., and K.R.W. wrote the paper.

• The authors declare no conflict of interest.

• Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo(accession no. GSE36398).

• This article contains supporting information online atwww.pnas.org/lookup/suppl/doi:10.1073/pnas.1209508109/-/DCSupplemental.

  http://www.pnas.org/content/early/2012/09/14/1209508109.abstract