Unique Mutation Found in Amyloid Diseases Sheds Light on Potential Treatment


Researchers have identified a unique mutation in a deceased transthyretin (TTR) amyloidosis patient, which sheds light on the disease and may help identify new targets for treatment.

Characterized by production of the abnormal amyloid protein, amyloidosis includes a group of rare disease subtypes in which amyloid protein fibers attach and collect in organs, tissues, nerves, and other locations throughout the body. Transthyretin (TTR) amyloidosis, which includes amyloid protein buildup mostly in the peripheral nervous system, is one of the multiple subtypes. Due to delays in diagnosis and limitations in effective treatments, TTR amyloidosis oftentimes leads to death.

However, researchers from the Boston University School of Medicine have discovered a unique duplication mutation in a deceased transthyretin (TTR) amyloidosis patient, a discovery that not only offers new insight into the disease, but also identifies new targets for potential treatment. Their study was published in the journal Proceedings of the National Academy of Sciences.

While stabilizing the structure of a mutated protein to prevent its misfolding may work for many patients with familial TTR amyloidosis through the use of the small-molecule drug diflunisal, the deceased patient who exhibited the Glu51_Ser52dup mutation did not respond to the treatment approach, according to the provider who treated the patient, John Berk, MD, associate clinical director of the Amyloid Treatment and Research Program at Boston University School of Medicine (BUSM).

"Studying those who do not respond to treatment provides critical insights into the molecular basis of the disease and offers new strategies for better treatments," he said in a recent statement.

In an effort better understand why the patient did not respond to the treatment for the disease, lead author and research scientist at Boston University School of Medicine (BUSM), Elena Klimtchuk, PhD, set to work on developing recombinant proteins that would essentially imitate normal transthyretin and its disease-causing variants.

The researchers further evaluated the proteins using several biophysical, biochemical and bioinformatics methods, and found that the mutation significantly destabilized the protein and encouraged amyloid formation in the face of small-molecule drug diflunisal treatment, which failed to block the process.

Specifically, the duplication was not found to alter the protein secondary or tertiary structure. Instead, it decreased the stability of the TTR monomer and tetramer, the study authors write. Diflunisal, which bound with near-micromolar affinity, only partially restored tetramer stability. The mutation was not found to have a significant effect on the free energy and enthalpy of diflunisal binding, and thus, on the drug—protein interaction.

"We were surprised to find that the mutation had little, if any, effect on the drug binding to its target protein, TTR,” corresponding author Olga Gursky, PhD, professor of Physiology and Biophysics at BUSM added. “We suspect that a higher dose of this drug is unlikely to help patients with this gene mutation.”

The authors added that the duplication induced tryptic digestion of TTR at near-physiological conditions, thus releasing a C-terminal fragment 49—129 which formed amyloid fibrils under conditions in which the full-length protein did not.

Amyloid deposits are comprised of such C-terminal fragments in addition to the full-length TTR in vivo. Furthermore, the Glu51_Ser52dup duplication, which was contained in the surface loop, assisted in making amyloid-forming fragments and decreasing structural protection in the amyloidogenic residue segment 25—34, working to promote the misfolding of the full-length protein.

“Our studies of a unique duplication mutation explain its diflunisal-resistant nature, identify misfolding pathways for amyloidogenic TTR variants, and provide therapeutic targets to inhibit amyloid fibril formation by variant TTR,” the study authors conclude.

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