You may not have heard of spinocerebellar ataxia 4 (SCA4). It is rare and it is a devastating movement disease. SCA4 generally begins when a person is 40 or 50, but it may occasionally begin in late teens.
A 25 Year Search
As reported to Utah Health, Utah’s Eccles research team led by Dr. Stefan Pulst and Dr. Pattie Figueroa collaborated with a multinational staff of researchers. The teams were able to identify the genetic differences that cause SCA4. Dr. Pulst, who has been studying the disease since 2010, said that after meeting so many patients and their families his mission became a “personal quest.” Currently there is no cure for SCA4 and until recently there was no explanation for the cause of the disease. The findings were reported in the Nature Genetics journal.
Importance of Repetition
Although repetitive DNA is normally part of the genome, in some instances it may be a threat to good health. The first indication of the disease begins with common signs such as difficulty with balance and walking. These symptoms become worse over time.
The scientists were aware that SCA4 was genetic. They were also aware that previous research had found the gene that was responsible for a specific area of one chromosome. However, the specific area was crowded with repeated segments that looked like other chromosomes. It also had a unique chemical element that has been the cause of many genetic failures. To improve their knowledge of the cause of SCA4, the researchers turned to a newly-developed sequencing technology.
They compared DNA from Utah families that were both unaffected and affected. They discovered that the ZFHX3 gene is unusually long and contains an especially long string of repetitive DNA.
The researchers reported that part of a gene named ZFHX3 is longer than the norm in SCA4 patients and also contains similar repetitive DNA. The team observed that isolated cells with the long repetitive DNA string appear to be weak and do not recycle proteins properly. The teams observed that some also contain protein clumps.
A Simple Explanation to a Complex Problem
Two thirds of the human genome is composed of repetitive sequences. Dr. Pulst explains that healthy cells must continuously dismantle proteins that do not function properly. He describes the mutation that causes SCA4 as a toxic repeat and suspects that it may distort the way a cell approaches misfolded or unfolded proteins.
The teams used cells from patients with SCA4 to demonstrate that the mutation is interfering with the protein-recycling process and possibly poisoning nerve cells. Researchers are also testing a therapy for the SCA2 mutation which, if successful, will impact SCA4 patients.
Dr. Figueroa, the study’s first author, said that although developing a treatment is a long process, with this discovery patients can learn if they are affected by the disease. This helps families make informed life decisions. The doctors emphasized that their discovery was possible thanks to the cooperation of the patients’ families. The teams traced the disease to a family of pioneers who had settled in Salt Lake Valley circa 1840.
