IPeople with a movement disorder called ataxia suffer from muscle weakness and poor balance and coordination. Although scientists have identified the genetic causes of some types of ataxia, which result from gene mutations, the causes of many ataxias remain a mystery. Causes of spinocerebellar ataxia type 4 (SCA4) is a rare type of ataxia that was discovered in 1996 on chromosome 16. The specific mutation responsible eluded scientists for decades, until now.1
Now, more than 20 years later, researchers Focused on mutations The gene zinc finger homeobox protein 3 (Model number), a transcriptional regulator that appears to inhibit a cell’s ability to undergo autophagy.2 The results of the study are: Nature Geneticswhich could help clinicians improve diagnosis and develop new treatments for similar conditions.
In 2007, Stephen ProustWhen Palst, a clinical neurologist at the University of Utah, met with the patients in the first study, he saw this as a rare opportunity to pinpoint a specific genetic cause of SCA4. “We had identified a lot of the ataxia genes, so we assumed this one would be relatively easy to find,” Palst says. “That wasn’t the case. It’s only now taken us a long time to identify the actual cause.” […] mutation.”
For decades, traditional sequencing had failed to reveal the mutations associated with the disease because the region is rich in glycine and cysteine ​​and particularly difficult to sequence, containing many duplications and pseudogenes. Instead, Palst’s team turned to long-read, single-stranded, whole-genome sequencing. When they scanned the genomes of SCA4 patients from the Utah patient’s family trees, one genetic fingerprint caught their attention: it was full of glycine repeats, called GGC expansions, and located in a region that codes for genes. Model numberwhich acts as a tumor suppressor. Excess GGC repeats, a type of nucleotide expansion, lead to toxic protein aggregates and are usually associated with certain diseases such as Huntington’s disease.
When the researchers looked at other families with Swedish roots, they found the same mutation, providing further evidence that it is linked to SCA4.
Once they had identified the mutations, Palst’s team tested their effects on cell function. When the researchers introduced the mutations into fibroblasts or induced pluripotent stem cells, they found that the cells had reduced autophagy compared to normal cells. In contrast, inhibiting ZFHX3 in cells with the mutations restored autophagy markers. The mutations “impair the cells’ self-digestion mechanism, and a lot of proteins build up,” Palst said. “You have a garbage problem.”
When the researchers then re-examined the brains of patients with cerebellar atrophy, they found that the brains were permeated with clumps of proteins called inclusions, evidence of a garbage problem in the brain. When they stained for the ZFHX3 protein, the inclusions glowed. The inclusions, which were not present in tissue from healthy people, expressed additional autophagy markers, including ubiquitin and p62.
“this is, [SCA4],” Said Martin Pauker“The inclusion bodies are strong evidence that this is a nucleotide expansion disease,” added Pauker, a neurologist at Karolinska Institutet who was not involved in the study.
Recently, Pauker’s team validated the findings. paper Published in Journal of Internal MedicineThe researchers found the same mutation in individuals from a Swedish family with SCA4.3 Palst said SCA4 “appears to be part of a growing class of neurological disorders caused by repeat expansions.”
The discovery could improve diagnosis and potentially help uncover commonalities between these diseases and develop new treatments. ZHFX3 The gene or the mechanism by which it alters cellular processes to cause neurological dysfunction.
Still, the discovery moves the field forward. “For us, this is a milestone,” Pauker says. “It concludes 20 years of research.”
