Distinctive patterns of microRNA expression in primary muscular disorders

doi:10.1073/pnas.0708115104

Distinctive patterns of microRNA expression in primary muscular disorders

^aHoward Hughes Medical Institute,
^bProgram in Genomics, Division of Genetics,
^cInformatics Program, and
Departments of ^gPathology and
^hNeurology, Children's Hospital, Harvard Medical School, Boston, MA 02115;
^dDepartment of Neuromuscular Research, National Institute of Neuroscience, Tokyo 187-8502, Japan;
^eDepartment of Neurology, University of Milan, 20122 Milan, Italy;
^fDepartment of Neurology, Brigham and Women's Hospital, Boston, MA 02115;
ⁱInstitute for Neuromuscular Research, The Children's Hospital at Westmead, New South Wales 2145, Australia;
^jGoldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem 91240, Israel;
^kDepartment of Human Genetics, University of Utah, Salt Lake City, UT 84132; and
^lUS Genomics, Woburn, MA 01801

Contributed by Louis M. Kunkel, August 30, 2007 (received for review July 25, 2007)

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Fig. 1.
miRNAs common to various muscular disorders. The list includes 55 commonly dysregulated miRNAs in five or more types of muscular disorders. A color scale represents the relative intensity of the expression signal by means of fold change compared with the control group, with gray indicating high expression and red low expression. For a complete list see SI Table 4.
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Fig. 2.
Unsupervised hierarchical clustering and PCA of miRNA expression differentiate DMD from normal muscle. Sixty miRNAs with significantly different expression between DMD (n = 8, D) and normal individuals (n = 9, B) were identified by ANOVA. (a) Hierarchical clustering of 17 samples and 60 genes. Each row represents an individual, and each column represents an miRNA gene. A color code represents the relative intensity of the expression signal, with red indicating high expression and green indicating low expression. (b) PCA of ANOVA-selected miRNAs. In this plot, the first principle components (PC1) axis accounted for 28.7% of the variance in the data set and is a result of noise, possibly introduced by different muscle types and genders. The second principle component (PC2) accounts for 15.1% of the variance and segregates DMD from normal individuals. BMD samples (n = 6) are found as intermediate between DMD and normal muscle, with a distribution consistent with their phenotypic characteristics. The profiles from more severely affected patients (BMD49377 and BMD89026) are found with those of DMD patients, whereas the mildly affected BMD patients (BMD29 and BMD4620) are close to normal muscle.
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Fig. 3.
Overrepresented miRNA regulatory pathways in primary muscular disorders. Fisher's exact test was used to identify significant enrichment for pathway annotations among predicted targets of the dysregulated miRNAs in the different diseases. Each column corresponds to a single disease, and each row corresponds to a KEGG pathway with an overrepresentation of miRNA targets. Pathways have been grouped in larger functional categories according to the KEGG annotation. Only pathways with at least one significant association are shown, and the confidence for enrichment of targets in a given pathway is shown by color-coding the P value ranges.