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Researchers tease the root cause of catastrophic genetic diseases

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Tuberous sclerosis (TSC) afflicts as many as 2 million people worldwide and affects multiple organs such as the lungs, brain, skin and kidneys. In about 80% of cases, cysts and benign tumors form in the kidney, eventually leading to renal failure.

The disease is known to be caused by genetic mutations, but it has not been well understood how these mutations lead to the formation of renal cysts.

Manoocher Soleimani, MD, a nephrologist who is a professor of internal medicine at the University of New Mexico, led a team that solved puzzles and showed the way to a potential cure for this catastrophic condition.

In a treatise published this week Minutes of the National Academy of Sciences, Soleimani and his colleagues report that the cause is an unexpected change in the composition and function of the cells that line the collecting ducts that inject fluid from the kidneys into the urethra.

“The kidneys form cysts in this disease, which continue to grow and grow larger,” says Soleimani. “There is no good cure.”

A class of drugs called mTOR inhibitors can shrink cysts in about half of the treated patients, but the other half do not respond, he says. And when treatment is discontinued, the cysts return and eventually lead to renal failure.

In exploring how mutations form and grow cysts, UNM, the Albuquerque Veterans Medical Center, Harvard University, the University of Cincinnati, and the University of Tennessee’s Soleimani et al. Focused on cells. The inserted cell. In a healthy kidney, the major cells are involved in the transport of fluid and the inserted cells secrete acid.

The Soleimani team used a knockout strain of specially bred mice to simulate the effects of TSC gene mutations in major cells and examined cysts formed in the kidney.

“We thought that the cells that line the cyst were the main cells,” says Soleimani. “We were completely wrong! 95% of the cells that lined the cyst were made up of inserted cells. This is completely unexpected and has never been reported.”

Still, strangers began to behave differently as the cyst sprouted and grew into a fluid-filled sac, with genetically normal inserts excreting fluid as well as acid. “They were genetically normal, but they were functioning in an unusual way,” says Soleimani.

Investigating this issue further, the team designed a double knockout mouse that lacked both the original cyst-driven mutation and a key gene that promotes acid secretion in the collecting duct. “Surprisingly, we found that one double knockout mouse model reduced the size and number of cysts by 85-90%, and another double knockout model completely prevented it,” he says.

Focusing on acid-secreting genes “opens new avenues” for potential treatments, according to Soleimani. This is because existing FDA-approved drugs are known to suppress their function.

Solei Mani, who also provides clinical care at VA Medical Center and UNM Hospital, was recently funded by the US Department of Veterans Affairs for further research on TSC kidney cysts.

“We are proposing to use drugs to manipulate the activity of these molecules,” he says. “First we do it in mice, but then we work with a doctor who cares for TSC patients and then move on to try these drugs in humans.”


Recreating the pathophysiology of polycystic kidney disease from human iPS cells


For more information:
Sharon Barone et al, renal inserter and transcription factor FOXi1, promote cyst formation in the tuberous sclerosis complex. Minutes of the National Academy of Sciences (2021). DOI: 10.1073 / pnas.2020190118

Courtesy of the University of New Mexico Health Sciences Center

Quote: Researcher found catastrophic genetic disease (February 4, 2021) obtained on February 4, 2021 from https://medicalxpress.com/news/2021-02-root-devastating-genetic-disease.html Make fun of the root cause of the day)

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Researchers tease the root cause of catastrophic genetic diseases

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