The TTR gene provides instructions for making the transthyretin protein, primarily produced in the liver. This protein circulates throughout the body, playing a role in various bodily functions. Understanding the TTR gene and its protein helps comprehend how it can lead to certain health conditions.
Normal Function of the TTR Protein
The transthyretin protein performs two main functions. It transports the thyroid hormone thyroxine and retinol (a form of vitamin A) through the bloodstream. To carry thyroxine, four transthyretin proteins assemble into a tetramer.
For retinol transport, the transthyretin tetramer also binds to retinol-binding protein. This ensures these important substances reach the tissues and cells where they are needed. While primarily made in the liver, a smaller amount is also produced in the brain’s choroid plexus and the eye’s retina.
TTR Gene Mutations and Disease
Mutations in the TTR gene alter the instructions for building the transthyretin protein, leading to structural changes. These altered proteins become unstable and misfold. Instead of maintaining their normal tetramer shape, they break apart and clump together to form insoluble strands called amyloid fibrils.
The accumulation of these amyloid fibrils in various organs causes transthyretin amyloidosis (ATTR amyloidosis). There are two primary types: Hereditary ATTR (hATTR) amyloidosis results from an inherited TTR gene mutation. Wild-type ATTR (wtATTR) amyloidosis develops when the normal transthyretin protein misfolds, typically due to aging. While hATTR can manifest at various ages, wtATTR most commonly affects men over 60, with average onset around 75. Each mutation can influence the disease’s onset, symptoms, and progression.
Symptoms and Manifestations of ATTR Amyloidosis
Amyloid fibril deposits in ATTR amyloidosis can affect multiple organs, leading to a range of symptoms. Two common presentations are cardiomyopathy and polyneuropathy. Cardiomyopathy occurs when amyloid builds up in the heart muscle, causing it to thicken and stiffen. This impairs the heart’s ability to pump blood effectively, potentially leading to symptoms like shortness of breath, fatigue, leg swelling, and abnormal heart rhythms. In advanced stages, it can result in heart failure.
Polyneuropathy involves amyloid deposition in the peripheral nerves. Nerve involvement can cause pain, numbness, and tingling sensations, often starting in the hands and feet. As the condition progresses, it may lead to muscle weakness, difficulty with walking, and a loss of sensation to temperature. Deposits can also affect the autonomic nervous system, which controls involuntary bodily functions, potentially causing digestive issues, dizziness upon standing, and sexual dysfunction.
Genetic Inheritance and Testing
Hereditary ATTR (hATTR) amyloidosis follows an autosomal dominant inheritance pattern. This means inheriting one copy of the mutated TTR gene from a single parent puts a person at risk. Each child of an individual carrying a TTR pathogenic variant has a 50% chance of inheriting that variant. Not everyone who inherits a TTR gene mutation will develop symptoms, a concept known as incomplete penetrance.
Genetic testing serves a dual purpose in managing hATTR amyloidosis. It confirms diagnosis in symptomatic individuals by identifying the specific TTR gene variant. For families with a known history, testing can identify at-risk individuals before symptoms appear, allowing for earlier monitoring and intervention.
Therapeutic Approaches for TTR Amyloidosis
Current therapeutic strategies for ATTR amyloidosis aim to interfere with the disease process at different stages. One approach involves TTR stabilizers, which are small molecules designed to bind to the transthyretin protein and prevent it from misfolding and dissociating from its stable tetramer form. By maintaining the protein’s proper structure, these therapies reduce the formation of amyloid fibrils.
Another category of treatments includes gene silencers, such as RNA interference (RNAi) therapies or antisense oligonucleotides (ASOs). These therapies work by reducing the liver’s production of the transthyretin protein. They achieve this by targeting and degrading the messenger RNA (mRNA) that carries the instructions for making transthyretin, thereby limiting the supply of the protein available to misfold.
A third area of development focuses on amyloid removers, which are therapies designed to clear existing amyloid deposits from tissues. These often involve monoclonal antibodies that specifically target and help remove the accumulated amyloid fibrils. While TTR stabilizers and gene silencers aim to prevent further amyloid formation, amyloid removers offer the prospect of addressing the already deposited material.