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Published on: July 23, 2012
MicroRNAs as Biomarkers of Charcot-Marie-Tooth Disease Type 1A
Hongge Wang1, Matthew Davison1, Kathryn Wang1
1From Translational Sciences (H.W., M.D., K.W., T.X., K.M.C.), Sanofi Research; Biostatistics and Programming (J.L.), Sanofi Development, Framingham, MA; Department of Neurology (X.W., R.Z., A.B., Y.B., L.G., S.M.E.F., T.G., M.E.S.), Carver College of Medicine, University of Iowa, Iowa City; Department of Neuromuscular Diseases (A.M.R., M.M.R.), UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, University College London, UK; and Waisman Center and Department of Comparative Biosciences (J.S.), University of Wisconsin, Madison.
Objective:
To determine whether microRNAs (miRs) are elevated in the plasma of individuals with the inherited peripheral neuropathy Charcot-Marie-Tooth disease type 1A (CMT1A), miR profiling was employed to compare control and CMT1A plasma.
Methods:
We performed a screen of CMT1A and control plasma samples to identify miRs that are elevated in CMT1A using next-generation sequencing, followed by validation of selected miRs by quantitative PCR, and correlation with protein biomarkers and clinical data: Rasch-modified CMT Examination and Neuropathy Scores, ulnar compound muscle action potentials, and motor nerve conduction velocities.
Results:
After an initial pilot screen, a broader screen confirmed elevated levels of several muscle-associated miRNAs (miR1, -133a, -133b, and -206, known as myomiRs) along with a set of miRs that are highly expressed in Schwann cells of peripheral nerve. Comparison to other candidate biomarkers for CMT1A (e.g., neurofilament light) measured on the same sample set shows a comparable elevation of several miRs (e.g., miR133a, -206, -223) and ability to discriminate cases from controls. Neurofilament light levels were most highly correlated with miR133a. In addition, the putative Schwann cell miRs (e.g., miR223, -199a, -328, -409, -431) correlate with the recently described transmembrane protease serine 5 (TMPRSS5) protein biomarker that is most highly expressed in Schwann cells and also elevated in CMT1A plasma.
Conclusions:
These studies identify a set of miRs that are candidate biomarkers for clinical trials in CMT1A. Some of the miRs may reflect Schwann cell processes that underlie the pathogenesis of the disease.
Classification Of Evidence:
This study provides Class III evidence that a set of plasma miRs are elevated in patients with CMT1A.
Insights
Plasma microRNAs (miRs) are elevated in Charcot-Marie-Tooth disease type 1A (CMT1A). These myomiRs and Schwann cell-associated miRs show potential as biomarkers for CMT1A clinical trials.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Charcot-Marie-Tooth disease type 1A (CMT1A) is an inherited peripheral neuropathy.
- Identifying reliable biomarkers for CMT1A is crucial for diagnosis and therapeutic development.
Purpose of the Study:
- To investigate whether specific microRNAs (miRs) are elevated in the plasma of individuals with CMT1A.
- To identify potential plasma-based biomarkers for CMT1A.
Main Methods:
- Plasma samples from CMT1A patients and controls were analyzed using next-generation sequencing for miR profiling.
- Elevated miRs were validated using quantitative PCR.
- Correlations between miRs, protein biomarkers (e.g., neurofilament light, TMPRSS5), and clinical data were assessed.
Main Results:
- Several muscle-associated miRs (myomiRs) and Schwann cell-specific miRs were found to be elevated in CMT1A plasma.
- Some elevated miRs demonstrated comparable or superior ability to discriminate CMT1A cases from controls compared to neurofilament light.
- Putative Schwann cell miRs correlated with the TMPRSS5 protein biomarker.
Conclusions:
- A panel of plasma miRs are identified as potential biomarkers for CMT1A.
- These miRs may offer insights into the underlying Schwann cellpathogenesis of CMT1A.
- The findings support the utility of these miRs in future CMT1A clinical trials.
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