Researchers Uncover Genetic Cause of Rare Neurological Disease

Rare Daily Staff

A multinational study by scientists at the University of Utah has identified the genetic cause of the rare, progressive neurological disease known as spinocerebellar ataxia.

The study, published in the journal Nature Genetics, opens the door for potential treatments.

Spinocerebellar ataxia 4 (SCA4) begins as difficulty walking and balancing, which gets worse as time progresses. The symptoms usually start in a person’s forties or fifties but can begin as early as the late teens. There is no known cure and the cause had been unknown.

SCA4’s pattern of inheritance had long made it clear that the disease was genetic, and previous research had located the gene responsible to a specific region of one chromosome. But that region proved difficult for researchers to analyze because it was full of repeated segments that look like parts of other chromosomes and has an unusual chemical makeup that causes most genetic tests to fail.

To identify the change that causes SCA4, the research team used a recently developed advanced sequencing technology. By comparing DNA from affected and unaffected people from several Utah families, they found that in SCA4 patients, a section in a gene called ZFHX3 is much longer than it should be, containing an extra-long string of repetitive DNA.

Isolated human cells that have the extra-long version of ZFHX3 show signs of being sick—they don’t seem able to recycle proteins as well as they should, and some of them contain clumps of stuck-together protein.

“This mutation is a toxic expanded repeat and we think that it actually jams up how a cell deals with unfolded or misfolded proteins,” said Stefan Pulst, professor and chair of neurology at the University of Utah and the last author on the study. “Healthy cells need to constantly break down non-functional proteins. Using cells from SCA4 patients, the group showed that the SCA4-causing mutation gums up the works of cells’ protein-recycling machinery in a way that could poison nerve cells.”

The researcher said finding the genetic change that leads to SCA4 will allow affected families to learn whether they have the disease-causing genetic change or not, which can help inform life decisions such as family planning, as well as lead to new treatments.

“The only step to really improve the life of patients with inherited disease is to find out what the primary cause is,” said Pulst. “We now can attack the effects of this mutation potentially at multiple levels.”

Photo: tefan Pulst, professor and chair of neurology at the University of Utah