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Basics of proteins and genetics
Proteins are essential components of the human body which are responsible for a diverse range of biologic functions. Proteins exist both within and outside of cells. Proteins are made up of subunits called amino acids. Combinations of 20 amino acids make up all of the proteins that are found in the body. Amino acids are naturally occurring substances that play a major role in many basic bodily functions. The basic order or sequence of amino acids defines a specific protein and that sequence is defined within our human DNA.
Proteins exist in our body in three-dimensional shapes. This overall shape is defined by the basic sequence on amino acids that make up that specific protein. This three-dimensional shape often includes a series of foldings that occur as the protein is formed. The shape of the protein is critical in its ability to carry out the task it has been created to do. If the shape of the protein changes, it may not be able to perform its role.
Certain genetic diseases may result in the creation of proteins that lose their shape or do not have the ability to fold into their normal three-dimensional shapes. These diseases are a result of a defect in one’s genes which we inherited from our parents.
References:
- National Center for Biotechnology Information (NCBI). Molecular modeling: a method for unraveling protein structure and function. Available at: http://www.ncbi.nlm.nih.gov/About/primer/molecularmod.html
- Pasternak, J.J. Chapter 4: The Molecular Biology of the Gene. Introduction to Human Molecular Genetics: Mechanisms of Inherited Diseases – 2nd Edition. January 2005; 75-106.
- Rees, A.R., Stermberg, M.J. From Cells to Atoms: an Illustrated Introduction to Molecular Biology. Palo Alto, CA: Blackwell Scientific Publications; 1984.
Transthyretin
Transthyretin is a protein routinely made by the liver. This protein is found in the blood and in the brain. Its role in the body is to assist in the transport or movement of other molecules in the blood. Transthyretin carries thyroxin (thyroid hormone) and retinol (Vitamin A).
The transthyretin protein is made up of four identical components, or monomers, which form a four component unit called a tetramer. In order for transthyretin to be able to carry thyroxin and retinol, it must be in the tetramer form.
References:
- Benson, M.D., Kincaid, J.C., Muscle and Nerve 2007; 36: 411-423
Transthyretin Amyloidosis
Transthyretin Amyoidosis is a genetically inherited disease that occurs due to an abnormality in the basic amino acid structure of the protein transthyretin. Because of a single error, or mutation, in the basic structure of this protein, the protein cannot stay in its normal three-dimensional tetramer form but breaks apart into the single monomer components. These individual monomers tend to clump together to form a structure called amyloid which ultimately ends up being deposited in the nervous system, heart, gastrointestinal tract and other organs of individuals who have this genetic defect.
At present it is known that there are approximately 100 different errors, or mutations, in the transthyretin gene. The majority of these mutations result in disease. The signs and symptoms of that disease are related to the places in the body where the amyloid is deposited and the damage it causes to that tissue or organ.
Transthyretin Amyloidosis is a rare disease which affects approximately 8,000 - 10,000 persons around the world. There are a few endemic areas of the world where families with this disorder are more likely to be found, including Portugal, Sweden and Japan. Most of the patients with this disorder are outside of these areas in the non-endemic regions of Europe, South America and the United States.
References:
- Benson, M.D., Kincaid, J.C., Muscle and Nerve 2007; 36: 411-423
How it Affects You
Transthyretin Amyloidosis with Polyneuropathy
As mentioned above, abnormalities in the transthryretin protein can result in the development of amyloid which leads to specific disease. There is a type of transthyretin amyloidosis that primarily affects the peripheral nerves in the body resulting in what is called polyneuropathy.
Polyneuropathy is a disease or malfunction of the peripheral nerves of the body which exist outside of the brain and spinal cord. These are the nerves that are responsible for a person’s ability to sense pain, temperature, position as well as to move one’s muscles.
Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) results from one of the most common genetic mutations associated with this disease. It is also known as Familial Amyloid Polyneuropathy (FAP). In this type of the disease, patients have the onset of symptom in their 30’s or 40’s. The main feature of this type of the disease is pain or loss of sensation in the feet and lower extremities which ultimately travels up the legs and then affects the upper extremities. As the disease progresses, patients will also begin to lose muscle strength and function in their extremities. Other parts of the nervous system can be affected which can result in dizziness/fainting, changes in heart rhythm and changes in the gastrointestinal and urogenital systems. Patient will likely develop diarrhea and/or constipation which may become severe. Male patients may develop erectile dysfunction and both men and women may develop problems urinating.
This disease is progressive and fatal and, at present, the only current treatment option is a liver transplant.
References:
- Benson, M.D., Kincaid, J.C., Muscle and Nerve. 2007; 36: 411-423
- Herlenius, G., Wilczek, H.E., Larsson, M. Transplantation. 2004; 77: 64-71
- Saraiva, M.J., Human Mutation. 2001; 17: 493-503
- Coehlo, T., Sousa, A., Lourenco, E., Ramalheira, J., Journal of Medical Genetics. 1994; 31: 293-299
- Miller, S.R., Sekijima, Y., Kelly, J.W., Laboratory Investigation. 2004; 84: 545-552
- Coutinho, P., Martins da Silva, A., Lopes-Lima, J., et al., Amsterdam:Excerpta Medica. 1980: 88-98
- Holmgren, G., Ericzon, B.G., Groth, C.G., Steen, L., Suhr, O. Andersen, O. et al., Lancet. 1993; 341: 1113-1116
Transthyretin Amyloidosis with Cardiomyopathy
In this type of transthyretin amyloidosis, it is the heart that is primarily affected by the deposition of abnormal amyloid protein. This type is called cardiomyopathy.
Cardiomyopathy is a disease that affects the muscle of the heart. As the heart muscle weakens, the ability of the heart to pump blood is affected and patients ultimately develop heart failure.
Transthyretin Familial Amyloid Cardiomyopathy (TTR-CM) results from a different genetic mutation of the transthyretin gene. Patients with this mutation will develop heart failure symptoms of shortness of breath, fainting, generalized fatigue and swelling (predominantly lower legs/ankles). Patients will typically develop symptoms after the age of 60 with this type of amyloidosis. This disease is usually treated symptomatically, for example diuretics (water pills) for ankle swelling.
References:
- Ikeda, S. Internal Medicine. 2004; 43: 1107-1114
- Hara, C.J., Falk, R.H. Amyloid. 2003 Jun; 10(2): 127-129
- Falk, R.H. Circulation. 2005 Sept; 112(13): 2047-2060. Review.
For any questions regarding the THAOS registry or other health-related information, please contact Pfizer Medical Information at 1-800-438-1985
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