Both genes have the same mutation, which leads to an excessive accumulation of protein within cells, and play a vital role in normal RNA functioning. The abnormal build-up of protein has been linked to cancer, specifically Ewing sarcoma, the second-most common type of bone cancer in teenagers and younger children.
RNA is the molecule that tells proteins how to assemble, based on DNA instructions.
The authors explain that their finding comes after several others that have pointed to common origins in cancer and degenerative diseases.
It appears that "unrelated" neurodegenerative diseases may share similar defects in RNA metabolism, the researchers found. They linked the problems in certain regions of the mutated proteins - nobody knows yet what their functions are.
J. Paul Taylor, M.D., Ph.D., one of the study authors, said:
"I hope this study helps to build the foundation for desperately needed treatments for ALS and perhaps a broad range of diseases caused by abnormal RNA metabolism."
About 5,600 patients are newly diagnosed with ALS in the USA each year. ALS is almost always fatal and the patient typically dies within five years. The sufferer experiences muscle wasting and paralysis that affects the arms and legs and trunk - their ability to walk, swallow and breathe deteriorates. There is currently no cure for ALS.
The scientists sequenced the exome which contains the instructions for making proteins. The exome is a portion of the genome which contains exons. They sequenced the exomes of two families whose members are affected by rare inherited degenerative disorders that target the cells in the brain, muscle and bone.
This study is a continuation of a project developed by the St. Jude Children's Hospital - Washington University Pediatric Cancer Genome Project, which has played a vital role in finding the mutations.
The scientists identified a previously unknown mutation in two RNA-binding proteins known as hnRNPA2B1 and hnRNPA1. Both the proteins bind RNA and help regulate its function.
When the authors checked for the same mutations in 517 patients, all of them with ALS, they found hnRNPA1 protein mutated in two of them. One had the inherited form of ALS. None of the other ALS patients had a family history of the disease.
Dr. Taylor said the new mutations were found in a region of the protein he refers to as a prion-like domain, because of its similarities with yeast proteins called prions. Prions, types of proteins, can alternate between shapes as different functions are required.
Taylor said "Until recently we did not know these domains existed in humans and now we realize that hundreds of human proteins have them. We're only beginning to understand their function in human cells."
The scientists showed that the prion-like domains are responsible for the changing shapes that occur when the proteins convert into fibrils (slender threads). The mutations speed up the formation of fibrils and recruit normal proteins to form fibrils. This type of propagation may be how ALS spreads throughout the nervous system, as well as other related diseases.
Taylor hypothesized that prion-like domains' normal function are to assemble RNAs into granules, types of temporary structures, which are part of the cell's normal machinery for producing protein.
In normal conditions, the granules do not last long and the RNA-binding proteins involved in forming them are recycled. However, in cells with the hnRNPA2B1 or hnRNPA1 mutation, the RNA granules were not disassembled and built up in the cytoplasm. "That's bad news for RNA regulation, which is bad news for those cells," Taylor explained.
Taylor said that their study may have several important implications. By knowing that the mutations have a negative impact on RNA regulation, this may lead to targeted treatments for ALS patients to correct the problem. The fact that the mutation is located in the prion-like domain may also prove significant. "Even though mutations in hnRNPA2B1 or hnRNPA1 are very uncommon, hundreds of other RNA-binding proteins have prion-like domains."
A patient with an unexplained neurodegenerative disease might have mutations in hnRNPA2B1 or hnRNPA1, Taylor added.
Saudi scientists identified a mutation on the SIGMAR1 gene associated with the development of ALS. They reported their findings in Annals of Neurology (August 2011 issue).
A biochemist from Purdue University determined that the function of a mutated gene that can lead to a genetic variation of ALS.
Written by Christian Nordqvist