Australians Find Compound That Prevents the Protein Misfolding Seen in Alport Syndrome

Alice Melão avatar

by Alice Melão |

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Hematuria and Alport

Chemical compounds known as small chaperone molecules can prevent the protein-structure abnormalities associated with the most common type of Alport syndrome, Australian researchers report.

This leads to normal production of the collagen protein that is missing in the disease.

Gene mutations cause collagen to misfold. Naturally occurring chaperone molecules prevent misfolding, but faulty genes disable them. Manmade chaperone molecules can overcome the problem.

The Australian study indicates that manmade chaperone molecules will work with X-linked Alport syndrome, the type that four-fifths of patients have and that is particularly severe in boys.

Researchers published their study in the journal Kidney International Reports. The title was “The Chemical Chaperone, PBA, Reduces ER Stress and Autophagy and Increases Collagen IV α5 Expression in Cultured Fibroblasts From Men With X-Linked Alport Syndrome and Missense Mutations.

Alport syndrome is a genetic disease that damages the kidneys and ultimately causes them to fail. It stems from mutations that affect the production of collagens, which are crucial to kidney function.

Scientists have found thousands of mutations of genes that encode collagen production, including more than 1,200 mutations of the COL4A5 gene.

About 40 percent of X-linked Alport syndrome patients have COL4A5 mutations that change the collagen IV α5 genetic sequence. The means the protein is unable to achieve the correct structure.

A lot of scientists believe we may be able to treat the disease with compounds that help collagen fold correctly.

University of Melbourne researchers wanted to see if the chaperone molecule PBA would prevent collagen misfolding in human Alport syndrome tissue grown in a lab. PBA is also known as 4-phenylbutyric acid.

They collected fibroblasts — cells that produce collagen — from the skin of two Alport patients with COL4A5 mutations and from three healthy volunteers.

The fibroblasts with COL4A5 mutations produced significantly less collagen IV α5 than healthy cells, the team discovered. They also multiplied more slowly than healthy cells. And they showed signs of metabolic stress, or an inability to convert food to energy.

When the team exposed the Alport patients’ cells to PBA,  the cells began producing more collagen. In addition, metabolic stress fell to levels seen in healthy cells.

The study showed that COL4A5 mutations associated with Alport syndrome lower fibroblasts’ collagen production, but that chaperone molecules such as PBA restore it.

“These results indicate novel pathogenetic mechanisms in Alport syndrome and further targets for therapy,” the researchers wrote. “In particular, PBA appears to have several potentially useful actions for the treatment of X-linked Alport syndrome.”


Jan avatar


Is there a clinical trial going on to test this? Where can I learn more?

Alice Melão avatar

Alice Melão

Dear Jan, from what I am aware there are no clinical trials testing such compounds. So far only proof-of-concept studies with animal models are being conducted to determine the full extent of effects of chemical chaperones. Hopefully this will trigger the development of new therapies that can be used in humans.

Zvonimir Kodba avatar

Zvonimir Kodba

Does it means that faulty collagen in human kidney cells are producing during whole life or just up to end of certain period of lif?
Is there any study for non x linked mutation on COL4A3 ?

Alice Melão avatar

Alice Melão

Due to the genetic nature of this disease the abnormal production of collagen happens since birth. Symptoms may only be detected later in life due to cumulative effects, and progression of the disease. You can find more information on COL4A3 mutations on our website

N rand Keller avatar

N rand Keller

Do experts know specifically what causes hearing loss and think these studies could eventually impact this.


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