C9orf72 Rantibody as a Diagnostic Test for C9orf72 Mutation Carriers

Technology #2012-253

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative diseases. FTLD results from the degeneration of the frontal and temporal lobes of the brain, and encompasses a group of disorders distinguished by abnormalities in behavior, language and personalityl. ALS is characterized by the degeneration of motor neurons, resulting in muscle weakness, spasticity, and atrophy. Because some FTLD patients develop movement abnormalities resembling ALS, and many ALS patients meet the criteria of FTLD, FTLD and ALS are believed to represent an overlapping continuum of disease. In fact, a recent groundbreaking study confirmed the genetic link between the two diseases, which many had postulated given that intracellular inclusions of TDP-43 have been observed in both ALS and FTLD-TDP. The discovery of an expansion of a hexanucleotide (GGGGCC) repeat in a noncoding region of C90RF72 is the most common known genetic cause of ALS and FTLD-TDP. We seek to elucidate how these expanded repeats contribute to disease pathogenesis in order to uncover new drug targets for treatment and in this case a specific biomarker for this genetic mutation. Unexpectedly, we discovered that GGGGCC repeat expansion expresses a novel dipolymeric poly-glycine-proline protein in the absence of a traditional ATG (methione) start codon which can be detected with our novel C90RF72 “RANTibody” (an antibody against the product of Repeat associated Non-ATG translation). Screening of several C9orf72 positive- and negative FLTD and ALS post-mortem cases as well as controls, found that this antibody is 100% specific for this genetic mutation (verified by PCR). These results have significant clinical relevance as a diagnostic tool for individuals who have this genetic mutation. Due the size and complexity of the GGGGCC hexanucleotide expansion, PCR methods to identify the mutation are fallible leading to false negatives. The C90RF72 RANTibodies offer and additional method to detect, in bodily fluids and/or peripheral tissues, the highly specific poly-glycine-proline product of the GGGGCC expansion.