TTR Variant, E61K, That’s Not Prone to Clumping Seen to Cause FAP in Other Ways

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by Joana Carvalho |

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Although less able to form damaging protein deposits, the E61K variant of transthyretin appears to cause familial amyloid polyneuropathy (FAP) through other mechanisms, a study suggested.

The study, “A low amyloidogenic E61K transthyretin mutation may cause familial amyloid polyneuropathy,” was published in the Journal of Neurochemistry.

Familial amyloid polyneuropathy (FAP), also known as hereditary transthyretin amyloidosis, is a rare progressive disease caused by genetic mutations in the TTR gene, which provides instructions for making a protein called transthyretin. These mutations change the normal structure of transthyretin, causing it to clump and form deposits of amyloid fibrils inside different tissues, particularly those of the heart and nerves.

Over time, these deposits can affect the function of peripheral nerves — those that control movement and sensation in the arms and legs — leading to peripheral neuropathy.

Nerves that control internal organs like the stomach and the heart may also be affected.  Patients here show symptoms of autonomic neuropathy, which can range from an irregular heart beat and drops in blood pressure, to incontinence or other bowel problems, and sexual dysfunction.

“However, the mechanisms underlying the preferential deposition of the variant TTR and peripheral neurodegeneration in FAP remain unknown,” investigators wrote.

Researchers in Japan described the clinical features of a late-onset form of FAP caused by the TTR variant known as E61K, which can cause sensory and autonomic neuropathy.

Previous studies on this disease form found that even though patients had a marked reduction in the number of peripheral nerve fibers, they showed no signs of amyloid deposits in their nerves.

After examining portions of the sural nerve — a sensory nerve that runs from the calf to the foot — of a patient with late-onset FAP caused by this variant, this team reached a similar conclusion.

Based on observations, they suggested this TTR variant might have low amyloidogenicity. That is, it might be less prone to form amyloid deposits.

To test this hypothesis, a series of lab tests were done to assess and compare E61K’s ability to form amyloid deposits to other TTR variants, including the normal form of the protein (wild-type TTR) and another mutant version (V30M TTR).

Test tubes with the three versions of TTR that were left for three days at a temperature of 37 C (98.6 F), showed the E61K variant formed fewer amyloid deposits than the V30M variant. The number of amyloid deposits formed by the wild-type version of the protein were identical to those observed with the E61K variant.

Next, investigators compared the neurotoxicity of the E61K variant with that of the V30M variant by placing both in contact with rat dorsal root ganglion (DRG) neurons. They examined how their extensions grew in the presence of these TTR variants.

Of note, DRG is a bundle of nerves emerging from the spinal cord that carry sensory information from the rest of the body to the central nervous system, the brain and spinal cord.

Here, only the V30M variant was found to prevent the growth of neuron extensions, by 18% compared to the E61K variant. There was no significant difference between E61K and the wild-type version of the protein.

“These findings argue against a direct neurotoxic effect of E61K TTR towards DRG neurons, and suggest that other mechanisms may underlie the sensory neurodegeneration in FAP TTR E61K,” the investigators wrote.

When investigators re-examined the sural nerve of the person whose FAP is due to the E61K variant, they found several signs indicative of Schwann cell death, which may also contribute to nerve cell loss. Schwann cells are a type of nerve cell that are responsible for producing myelin — the fatty sheath that wraps around and protects nerve fibers — in the peripheral nervous system.

“These findings suggest that E61K TTR is low amyloidogenic … [and] that TTR deposition in the DRG and Schwann cell apoptosis [programmed cell death] may play important roles in neurodegeneration in FAP,” the team concluded.