A bridged approach to novel gene discovery for Congenital Muscular Dystrophies (CMD)

Project: Research


  • Arunkanth Ankala (PI)


Congenital Muscular Dystrophy,CMD is the most poorly understood subtype of inherited Neuromuscular disorders and have a very early onset hypotonia. Though not all, majority of the CMD subtypes have been found to be associated with cardiac complications including cardiomyopathy and even congestive heart failure. Diagnosis of CMD is often very difficult and most patients face a diagnostic odyssey before receiving the appropriate clinical and molecular diagnosis. To date, 14 genes have been shown to be associated with CMD, however atleast 35 percent of patients with a diagnosis of CMD do not still get a molecular diagnosis. This could both be because of a novel gene or a novel genotype associated with the disease. With the rapid developments in technologies it is now possible to identify novel disease genes faster than ever before, which is the major aim of this proposal. Through an integrated approach using next generation genotyping, sequencing and microarray tools, we will not only discover the associated gene and genotype but also create a comprehensive map of the CMD muscle genome, transcriptome and proteome. Understanding the functional intricacy and the effect of mutation on the protein expression is critical to understanding the phenotype as well as making the right choice of therapeutic approach. Therefore a combined approach of cutting edge technologies at genomic, transcriptional, and proteomic levels will be applied towards identification of associated gene, its expression as well as proteomic profile of associated proteins. To this end, we will analyze a set of 20 patient samples with unknown forms of CMDs. To identify the causative genes and genotypes whole genome genotyping by Affymetrix 6.0 arrays, whole genome sequencing by Nimblegen Sequence capture and next generation sequencing by SoLiD will be performed on each sample. Gene expression levels using Affymetrix GeneST arrays and protein expression levels using antibody array analysis of known CMD related genes will be performed to evaluate the effect of the novel variants. This comprehensive understanding will aid in developing effective therapeutic strategies for CMD such as the antisense oligonucleotide therapy. Such comprehensive knowledge of the genotype-phenotype correlation will very likely blur the boundaries between different muscular dystrophies and may help in the development of more effective therapies as well as aid in personalized therapy.
Award amount$90,380.00
Award date07/01/2011
Program typePostdoctoral Fellowship
Award ID11POST7580072
Effective start/end date07/01/201106/30/2013