Identification of gene fusions associated with amyotrophic lateral sclerosis

Abstract

Genetics is an import risk factor for amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease affecting motor neurons. Recent findings demonstrate that, in addition to specific genetic mutations, structural variants caused by genetic instability can also play a causative role in ALS. Genomic instability can lead to deletions, duplications, insertions, inversions, and translocations in the genome, and these changes can sometimes lead to fusion of distinct genes into a single transcript. While such gene fusion events have been studied extensively in cancer, they have not been thoroughly investigated in ALS. We leveraged bulk RNA-Seq data from human post-mortem samples to determine whether fusion events occur in ALS. We report for the first time the presence of gene fusion events in several brain regions as well as in spinal cord samples in ALS. Although most gene fusions were intra-chromosomal events between neighboring genes and present in both ALS and control samples, there was a significant increase in the number of unique gene fusion in ALS compared to controls. Lastly, we have identified specific gene fusions with a significant burden in ALS, that were absent from both control samples and known cancer gene fusion databases. Collectively, our findings reveal an enrichment of gene fusion in ALS and suggest that these events may be an additional genetic cause linked to ALS pathogenesis.

The First Insight into the Hereditary Fusion Gene Landscape of Amyotrophic Lateral Sclerosis

“…ADAMTSL3-SH3GL3 , reported recently 20, 37 , was an inversion of SH3GL3-ADAMTSL3 38 on 15q25, encoding thirteen isoforms and coded for 42 alternatively-spliced isoforms (Fig.3). Its ADAMTSL3-SH3GL3 main isoform a was expressed only at 19% of the KANSARL (KANASL1-ARL17A) main isoform level and encoded a conceptual 202 aa ADAMTSL3-SH3GL3 fusion protein over two-thirds of which was from SH3GL3 .…”

“…Table 3 showed that SH3GL3-ADAMTSL3 was almost ubiquitously expressed in ASL, OND, AD, MTLE, and two controls. In comparison, it was detected in 7.5% of 133 GTEx brain cortexes and suggested that SH3GL3-ADAMTSL3 38 and ADAMTSL3-SH3GL3 20, 37 behaved similarly. Since SH3GL3-ADAMTSL3 EFG can be treated as a permanent HFG with a recurrent frequency of 100%, we speculated that ADAMTSL3-SH3GL3 had a much higher recurrent frequency than 1.5% of GTEx brain cortexes and was activated to be expressed by interactions between genetic and environmental lesions during aging.…”

“…Table 3 showed that SH3GL3-ADAMTSL3 was almost ubiquitously expressed in ASL, OND, AD, MTLE, and two controls. In comparison, it was detected in 7.5% of 133 GTEx brain cortexes and suggested that SH3GL3-ADAMTSL3 38 and ADAMTSL3-SH3GL3 20,37 behaved similarly.…”

“…Many studies have speculated that structural variants may be a source of missing ASL heritability 10, 19 . More recently, Raghav et al analyzed RNA-Seq data from Target ALS and the NYGC ALS Consortium and identified 607 unique fusion genes, some significantly higher in ASL samples than those in control 20 , suggesting that fusion genes generated by structural variants may be responsible for ASL.…”

In Silico Exploration of Metabolically Active Peptides as Potential Therapeutic Agents against Amyotrophic Lateral Sclerosis

“…Gene fusion usually involves deletion, insertion, translocation, inversion, or read-through transcription of adjacent genes [ 40 ]. Recently, several fusion genes have been identified from RNA-Seq data of ALS patients, including TVP23C–CDRT4, AC090517.5–ZNF280D, MAILR–ATP6V1C1 and C8orf44–SGK3 by neighbor fusion as well as YAF2–RYBP by inter-chromosomal fusion [ 41 ]. Based on the results of this study, the fusion of DCTN1-KIF5A requires further investigation.…”