TTR gene: hereditary transthyretin amyloidosis and ATTR CM

Once thought to be a rare genetic disease, new research shows that hereditary transthyretin amyloidosis (hATTR) may be more common, especially in people of African ancestry. The good news is that several new drugs are in clinical trials for hATTR. Understanding your genetic risk can help you seek treatment earlier before the damage is irreversible.

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Table of Contents

What does the TTR protein do?

The transthyretin (TTR) protein transports both thyroid hormone (T4, thyroxine) and retinol (a form of vitamin A) to the liver.

The protein is named transthyretin because it transports thyroxine (thyroid hormone) and retinol (vitamin A).

The TTR protein is made in the liver and in the choroid plexus, which is the region where cerebrospinal fluid is produced. It circulates through the bloodstream and the cerebrospinal fluid.

The thyroid secretes several different thyroid hormones. T4, or thyroxine, circulates bound to a protein — either bound to thyroid hormone-binding protein or bound to TTR.

Retinol, or vitamin A, is important in many biological functions, including regulating cell differentiation, neuron growth, and neuron survival. Retinol is transported in the bloodstream bound to retinol-binding protein and TTR. These two proteins together form a stable complex that keeps vitamin A from being broken down and excreted.[ref]

As you can see, the TTR protein has a couple of essential functions in the body.

Unfortunately, the TTR protein can also cause significant problems for a few people…

What is hATTR polyneuropathy?

Hereditary transthyretin amyloidosis (hATTR) is a genetic disease caused by mutations in the transthyretin (TTR) gene. These changes can impact the peripheral and autonomic nervous systems, as well as the cardiovascular system.

hATTR was formerly referred to as Transthyretin familial amyloid polyneuropathy (TTR-FAP) or transthyretin familial amyloid cardiomyopathy.

Extracellular deposition of the misfolded proteins (amyloids) causes hATTR symptoms.

The misfolded TTR proteins combine to form amyloid fibrils, causing cytotoxicity and tissue damage. The deposition of the amyloid fibrils in various tissues (nerve, heart, eyes, kidney, gastrointestinal mucosa) causes cellular damage and the subsequent symptoms of hATTR.

Quick terminology time-out:
Amyloid is a general term applied to misfolded proteins that create a certain type of structural change. The overarching term for diseases caused by amyloids is amyloidosis. There are about three dozen different amyloidosis diseases, each due to a different protein that misfolds and causes fibrils to form. The most well-known is amyloid-beta (misfolded APP protein) which is implicated in causing Alzheimer’s disease.[ref]

TTR polyneuropathy symptoms often begin before age 50.

hATTR symptoms include:

paresthesia (pins and needles or numbness in the skin)
burning sensations or numbness, usually starting in the feet
dysautonomic nervous system problems (bowel issues, impotence,
dysesthesia (weird, unpleasant touch sensations, kind of like pain)

hATTR CM – Heart Symptoms and other symptoms

TTR cardiac symptoms can include cardiomyopathy and arrhythmia.[ref]

Other symptoms can include problems in the eyes, kidneys, carpal tunnel syndrome, and gastrointestinal issues.

hATTR possible symptoms. PMC7041433 CC image.

What causes hATTR?

Mutations in the TTR gene cause the hereditary form of TTR amyloidosis. Currently, over 120 known mutations in the gene are linked to hATTR. Some mutations are more likely to result in heart issues, while others usually present with nerve problems first.[ref]

Certain mutations are more commonly found in ancestry groups and locations:

rs76992529, or VI122I, is most common in African Americans and people of West African descent
rs28933979, or V30M, is most common in people of Portuguese, Northern Swedish, and Japanese descent
rs121918070, or T60A, is most common in people of Irish and British descent.
rs267607161, or A117S, is found in Chinese Malaysians.[ref]

In addition to the hereditary form of amyloid TTR, some people without mutations in the gene can also end up with proteins that misfold and aggregate. It is known as wild-type ATTR or wild-type transthyretin amyloid and mainly affects the heart. Wild-type ATTR is more likely in the elderly.

TTR Genotype Report:

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*Important: Please note that AncestryDNA data is not FDA approved for reporting on hATTR. 23andMe data is quality approved by the FDA on the first three mutations listed below. Keep in mind that these mutations below are just the most common ones. There are more than a hundred other really rare TTR mutations that 23andMe or AncestryDNA does not cover. Always get a second, clinical-grade test before making any major health-related decisions.

Check your genetic data for rs28933979 V30M (23andMe v4, v5 – i3002758):

G/G: typical
A/G: TTR mutation

Members: Your genotype for rs28933979 is — or for i3002758 is —.

Check your genetic data for rs121918070 T60A (23andMe v4, v5 – i5004213):

A/A: typical
A/G: TTR mutation (found in up to 3% of African population groups)

Members: Your genotype for rs121918070 is — or for i5004213 is —.

Check your genetic data for rs76992529 V122I (23andMe v4, v5 – also i3002759):

G/G: typical
A/G: TTR mutation, often cardiac related

Members: Your genotype for rs76992529 is — or for i3002759 is —.

Check your genetic data for rs267607161 A117S (AncestryDNA*):

G/G: typical
G/T: TTR mutation

Members: Your genotype for rs267607161 is —.

Lifehacks:

If your genetic data shows a TTR mutation, talk with your doctor about testing to confirm.

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