Motor neuron connecting to muscle fiber to illustrate myasthenia gravis
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Spinocerebellar ataxia 4 (SCA4)’s genetic cause has been pinpointed using long-read single-strand whole-genome sequencing (LR-GS) on data from a large Utah population. Researchers found that SCA4 patients have a section in the gene ZFHX3 that contains a heterozygous GGC-repeat expansion, which makes it extra long. ZFHX3 is a zinc finger homeobox protein and is also known as AT-binding transcription factor 1 (ATBF1).

The team’s results are published in Nature Genetics. The multinational study was led by Stefan Pulst, MD, senior author of the study and chair of neurology, and K. Pattie Figueroa, a project manager in neurology. Both are affiliated with the Spencer Fox Eccles School of Medicine at University of Utah. 

SCA4 is a rare progressive neurological disease whose first sign is typically difficulty walking and balancing that gets worse over time. 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. 

Despite the finding of linkage to chromosome 16q in 1996, the mutation causing SCA4 long remained unknown. That region of the genome was difficult for researchers to analyze. It was full of repeated segments that look like parts of other chromosomes, and had an unusual chemical makeup that makes most genetic tests fail.

To pinpoint the change that causes SCA4, this team used LR-GS to compare DNA from affected and unaffected people from several Utah families. They started with one large Utah pedigree and ultimately queried 6,495 genome sequencing datasets and identified the repeat expansion in seven additional pedigrees.  

Isolated human cells that have the extra-long version of ZFHX3 don’t seem able to recycle proteins as well as they should, and some 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 Pulst. 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 researchers noted that something similar seems to be happening in another form of ataxia, spinocerebellar ataxia 2 (SCA2), which also interferes with protein recycling. The researchers are currently testing a potential therapy for SCA2 in clinical trials, and the similarities between the two conditions suggest the treatment might benefit patients with SCA4 as well.

Finding the genetic change that leads to SCA4 is essential to develop better treatments, Pulst said. “The only step to really improve the life of patients with inherited disease is to find out what the primary cause is. We now can attack the effects of this mutation potentially at multiple levels.”

Said Figueroa, “People in affected families can learn whether they have the disease-causing genetic change or not, which can help inform life decisions such as family planning. “They can come and get tested and they can have an answer, for better or for worse.”

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