After a quarter of a century of uncertainty, US scientists have finally uncovered the cause of a rare progressive neurological disease known as spinocerebellar ataxia 4 (SCA4).
For most people, the first sign is difficulty walking and balancing, which gets worse as time progresses. MedicalXpress reports that the symptoms usually start in a person’s 40s or 50s but can begin as early as in the late teens.
There is no known cure. And, until now, there was no known cause.
Now, a multinational study led by Dr Stefan Pulst, professor and chair of neurology, and Pattie Figueroa, a project manager in neurology, both in the Spencer Fox Eccles School of Medicine at the University of Utah, has conclusively identified the genetic difference that causes SCA4, bringing answers to families and opening the door to future treatments.
Their results were published in the journal Nature Genetics.
SCA4’s pattern of inheritance had long made it clear that the disease was genetic, and previous research had located the gene responsible for a specific region of one chromosome.
But that region proved extraordinarily difficult for researchers to analyse: full of repeated segments that look like parts of other chromosomes, and with an unusual chemical makeup that makes most genetic tests fail.
To pinpoint the change that causes SCA4, Figueroa and Pulst and 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 Pulst, 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.
Hope for the future
Intriguingly, something similar seems to be happening in another form of ataxia, 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 raise the possibility that 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.”
But while treatments will take a long time to develop, simply knowing the cause of the disease can be incredibly valuable for families affected by SCA4, said Figueroa, the first author on the study.
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 have an answer, for better or for worse,” she added.
The researchers emphasise that their discoveries would not have been possible without the generosity of SCA4 patients and their families, whose sharing of family records and biological samples allowed them to compare the DNA of affected and unaffected individuals.
Family records were complete enough that the researchers were able to trace the origins of the disease in Utah back through history to a pioneer couple who moved to Salt Lake Valley in the 1840s.
Since meeting so many families with the disease, studying SCA4 has become a personal quest, Figueroa added.
“I’ve been working on SCA4 directly since 2010 when the first family approached me …This is not just science. This is somebody’s life.”
Study details
A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy
Karla Figueroa, Caspar Gross, Elena Buena-Atienza et al.
Published in Nature Genetics on 29 April 2024
Abstract
Despite linkage to chromosome 16q in 1996, the mutation causing spinocerebellar ataxia type 4 (SCA4), a late-onset sensory and cerebellar ataxia, remained unknown. Here, using long-read single-strand whole-genome sequencing (LR-GS), we identified a heterozygous GGC-repeat expansion in a large Utah pedigree encoding polyglycine (polyG) in zinc finger homeobox protein 3 (ZFHX3), also known as AT-binding transcription factor 1 (ATBF1). We queried 6,495 genome sequencing datasets and identified the repeat expansion in seven additional pedigrees. Ultrarare DNA variants near the repeat expansion indicate a common distant founder event in Sweden. Intranuclear ZFHX3–p62–ubiquitin aggregates were abundant in SCA4 basis pontis neurons. In fibroblasts and induced pluripotent stem cells, the GGC expansion led to increased ZFHX3 protein levels and abnormal autophagy, which were normalised with small interfering RNA-mediated ZFHX3 knockdown in both cell types. Improving autophagy points to a therapeutic avenue for this novel polyG disease. The coding GGC-repeat expansion in an extremely G+C-rich region was not detectable by short-read whole-exome sequencing, which demonstrates the power of LR-GS for variant discovery.
See more from MedicalBrief archives:
Seven-year search for cause of dizziness