Genetic cause of rare neurological disease discovered after 25 years of research: ScienceAlert

You may not have heard of spinocerebellar ataxia type 4 (SCA4) because it is an incredibly rare disease, but after a quarter of a century of research, the genetic coding behind SCA4 has now been identified, potentially opening new treatment options for this serious disease. disease.

An international team of researchers behind the discovery claims to have identified for the first time the cause of this debilitating disease. People with SCA4 gradually develop worsening walking and balance problems, and there is currently no cure.

As SCA4 is clearly passed down from generation to generation, scientists knew genetics were involved, but it took the latest genome sequencing techniques and a search of 6,495 genome sequencing datasets to reveal that a section of A gene called ZFHX3 is the culprit behind the disease.

The ZFHX3 gene was identified using long-read genome sequencing, which, as the name suggests, allows for the identification of longer DNA fragments. ZFHX3 is found in an area of ​​DNA with many repeated segments, making it difficult to analyze.

Additionally, the mutation itself is one of these repeating segments.

“This mutation is a toxic expanded repeat and we think it blocks the way a cell processes unfolded or misfolded proteins,” says neurologist Stefan Pulst of the University of Utah.

Part of ZFHX3 is much longer than it should be in people who develop SCA4, the research team found, and cells with this extended version show signs of poor health – in particular, they don’t cannot do the essential work of recycling proteins as they should.

Further research showed that the ZFHX3 mutation blocked the protein recycling machinery, potentially leading to nerve cell poisoning and causing disabling symptoms that worsen as SCA4 takes hold.

The researchers would like to acknowledge the help they received from families affected by SCA4, without whom the new discovery would not have been possible. The team was able to trace the disease to the Salt Lake Valley in the 1840s.

“I have worked directly on SCA4 since 2010, when the first family approached me, and once you go to their house and get to know them, their number is no longer on the DNA vial,” explains the neurologist Karla Figueroa from the University of Utah.

“These are people you see every day…you can’t walk away. It’s not just science. It’s someone’s life.”

All types of spinocerebellar ataxia affect approximately 150,000 people in the United States (population 341.5 million), and the number of people with specific type 4 is considerably lower than that, but the new research means that people Affected people can be tested for the gene responsible for the disease. .

Later, treatments could be developed, we now know what triggers SCA4. Additionally, the researchers behind the new study believe that something similar might also happen with other types of spinocerebellar ataxia.

“The only step to truly improving the lives of patients with an inherited disease is to find out what the root cause is,” says Pulst. “We can now attack the effects of this mutation potentially on multiple levels.”

The research was published in Natural genetics.