C9orf72 and Other Novel Genes Implicated in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Fluorescence in situ hybridization (FISH) of c9FTD/ALS. The RNA foci in the nucleus (stained with DAPI, blue) is a frontal cortex neuron using a cyanine 3-labeled (GGCCCC)4 oligonucleotide probe (in red).

Fluorescence in situ hybridization (FISH) of c9FTD/ALS. The RNA foci in the nucleus (stained with DAPI, blue) is a frontal cortex neuron using a cyanine 3-labeled (GGCCCC)4 oligonucleotide probe (in red).

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are closely related conditions with overlapping clinical, genetic and neuropathological features. ALS and FTD often co-occur in the same family, and the prevalence of FTD in ALS populations may approach 40 percent. In 2011, the laboratory identified a GGGGCC hexanucleotide repeat expansion in the noncoding region of chromosome 9 open reading frame 72 (C9orf72) as the long-sought cause of FTD and ALS linked to chromosome 9p. Genetic studies now suggest that this repeat expansion is the most common cause of familial FTD and ALS, causing 25 percent of familial FTD cases, 30 percent of familial ALS cases and 1 to 5 percent of sporadic cases.

Expanding upon the laboratory's 2011 discovery, the team seeks to improve understanding of the clinical variability associated with C9orf72-linked ALS and FTD as well as identify disease modifying factors. The identification of C9orf72-specific biomarkers, or means to diagnose and measure disease progression, and the development of new therapies targeting these markers may significantly impact patient care.

While multiple disease mechanisms have been proposed, including a loss of C9orf72 expression and toxic gains-of-function via RNA aggregation in nuclear RNA foci and the generation of dipeptide repeat proteins, there are still many questions.

For example, it is unknown what determines whether mutation carriers develop FTD or ALS and whether symptoms will occur as early as 30 years of age or after the age of 70. To answer these questions and further study the clinical and biological effects of the C9orf72 repeat expansion and its impact on patients, the laboratory seeks to do the following:

  1. Characterize the repeat length and associated phenotypes of GGGGCC repeat expansions in C9orf72
  2. Identify genetic modifiers of disease onset or presentation in patients carrying GGGGCC repeat expansions in C9orf72
  3. Identify gene expression and alternative splicing changes resulting from GGGGCC repeat expansions in frozen brain tissue
  4. Systematically characterize C9orf72 mRNA expression in the prefrontal cortex, motor cortex and cerebellum by real-time PCR and northern blotting
  5. Investigate the association of C9orf72 repeat length, C9orf72 expression and transmembrane protein 106B genotype with penetrance, progression and clinical features in longitudinally followed c9ALS pedigrees

In addition to the laboratory's use of next-generation sequencing technology to identify other novel causal genes and genetic risk factors in ALS and FTD, this work is funded by multiple grants, including support from the ALS Therapy Alliance and a Milton Safenowitz Post Doctoral Fellowship for ALS Research from the ALS Association.