2021 Diseases caused by Protein Substitution and Deletion. There are many diseases which are caused by protein substitution and deletion. Akande Precious Anjolajesu Introduction to Biochemistry 12/4/2021 Table of Contents INTRODUCTION ................................................................................................................................................................. 3 THALASSEMIA ................................................................................................................................................................... 4 PHENYLKETONURIA........................................................................................................................................................... 6 TAY-SACHS DISEASES ........................................................................................................................................................ 8 SICKLE CELL ANEMIA ......................................................................................................................................................... 9 References ...................................................................................................................................................................... 10 2 INTRODUCTION Our DNA is found in the nucleus and consists of genes that code for polypeptides (protein). Protein is synthesised in the ribosome. The DNA sends messages of its code through the mRNA to the ribosome and then the rRNA translates so that amino acids are assembled by the tRNA to make proteins. Unfortunately, sometimes things go wrong with the coding and the protein formed is abnormal or not able to perform its actual function. This is errors are called Mutations or Gene variants. According to MedlinePlus genetics (2021) there are so many kinds and they have varying effects on health depending on when they occur and whether they alter the function of essential proteins. They include: Substitution: Here, one nucleotide is replaced with another. There are two types; in missense substitution the change in nucleotide results in the replacement of an amino acid with another in the protein made from the gene. The amino acid change then alters the function of the protein. In nonsense substitution, instead of a change in amino acids, the altered DNA results in a stop codon or signal that prematurely tells the cell to stop building a protein. This result to a shortened protein that may function improperly or break down (What kind of gene mutations are possible?: MedlinePlus genetics, 2021). Insertion: Here the DNA sequence changes by adding one or more nucleotides to the gene. As a result, the protein made may not function properly (What kind of gene mutations are possible?: MedlinePlus genetics, 2021). Deletion: This changes the DNA sequence by removing at least one nucleotide in a gene. It could be small deletion where only one or a few nucleotides are removed, while larger deletions involve the removal of an entire gene or neighbouring genes (What kind of gene mutations are possible?: MedlinePlus genetics, 2021). Deletion-Insertion/Insertion-Deletion: Here deletion and insertion happens at the same time in the same location in the gene. Here at least one nucleotide is removed and at least one nucleotide is inserted. The change is complex and different from a simple substitution (What kind of gene mutations are possible?: MedlinePlus genetics, 2021). Duplication: It occurs when a stretch of one or more nucleotides in a gene is repeated next to the original DNA sequence (What kind of gene mutations are possible?: MedlinePlus genetics, 2021). Inversion: Here more than one nucleotide is changed by replacing the original sequence with the same sequence in reverse order (What kind of gene mutations are possible?: MedlinePlus genetics, 2021). Frame shift: A frame consists of groups of three nucleotides that each code for one amino acid. A frame shift occurs when there is an addition or loss of nucleotides that shifts and changes the code for all downstream amino acids. The resulting protein is non-functional (What kind of gene mutations are possible?: MedlinePlus genetics, 2021). Because of this numerous errors during protein synthesis, the resulting proteins don’t function properly or could even become non functional resulting to different types of diseases. These diseases include: 1. 2. 3. 4. Thalassemia. Phenylketonuria. Tay-Sachs diseases. Sickle cell anemia. 3 THALASSEMIA Thalassemia is a hereditary blood disorder in which the body makes an abnormal form or inadequate amount of haemoglobin, a protein in red blood cells that carries oxygen (Thalassemia: MedlinePlus medical encyclopedia, 2021). When there isn’t enough haemoglobin, the body’s red blood cells don’t function properly and they last shorter periods of time, so there are fewer healthy red blood cells travelling in the bloodstream. Red blood cells carry oxygen, an important food like gas that cells use to function, to all the cells of the body. When there are not enough healthy red blood cells, there is also not enough oxygen delivered to all the other cells of the body. This result to weak or short breath, and feeling tired, a condition called anaemia. There are two things to look at when talking about types of thalassemia: The specific part of haemoglobin that is affected. The severity of thalassemia. The specific part that is affected:Hemoglobin consists of an iron containing heme ring and four globin chains: two alpha and two beta chains. So therefore there are two types of thalassemia here. Alpha Thalassemia: This is as a result of deficient or absent synthesis of alpha globin chains leading therefore to excess beta globin chains. This is caused by a protein deletion in one or more of the genes. A single gene deletion results in alpha thalassemia silent carrier status, a two-gene deletion causes alpha thalassemia trait (minor) and the three gene deletion results in significant production of hemoglobin H (alpha thalassemia intermedia) with four beta chains. The four gene deletion results in significant production of hemoglobin Bart’s with four gamma chains (alpha thalassemia major) (Muncie & Campbell, 2009). Beta Thalassemia: Here there is absent or deficient production of beta globin chains leading to excess alpha chains. It also caused by deletion of the genes involved in beta globin synthesis. It could be beta thalassemia trait minor (one gene defect), beta thalassemia major or beta thalassemia intermedia (Muncie & Campbell, 2009). The severity of thalassemia:There are words used to describe how severe thalassemia is (Centers for Disease Control and Prevention, 2020). The words majorly used are Traits: This also means minor. A person that has thalassemia traits usually has no symptoms at all (asymptomatic) or may have mild anemia. Intermedia: The symptoms are more serious than traits but less mild than major. A person with thalassemia intermedia could develop hemolytic anemia, a disorder where red blood cells are destroyed faster than they can be made. Major: This is the most severe type of thalassemia. It could result to fatal hydrops fetalis, severe hemolytic anemia, poor growth and skeletal abnormalities during infancy. Affected children will require lifelong blood transfusions. SYMPTOMS: People who have intermedia and major thalassemia usually find out about their condition during their childhood since they usually have symptoms of severe anemia early in life. On the other hand, people with trait or minor thalassemia may only find out because they are having symptoms of anemia or only if a doctor finds anemia during a routine blood test. Since thalassemia is inherited, the condition runs in the family, some people find out about their thalassemia because they have relatives with similar condition. For example, if person receives a beta thalassemia 4 trait from his father and another from his mother, he will have beta thalassemia major. If a person receives an alpha thalassemia trait from his mother and normal alpha parts from his father, he will have alpha thalassemia trait or minor (National Heart, Lung, and Blood Institute, 2020). Other health problems include: Slow growth and delayed puberty. Bone problems as bone marrow could expand causing the bones to become brittle and break easily. An enlarged spleen, liver or heart which will worsen anemia. Poor appetite. Dark urine (sign of red blood cells breaking down). Jaundice TREATMENT AND MANAGEMENT: Silent carriers of thalassemia (alpha or beta thalassemia trait) are asymptomatic and therefore require no treatment. For moderate and severe forms of thalassemia treatments include blood transfusions, iron chelation therapy and folic acid supplements. NOTE: The only cure to thalassemia is a blood and marrow stem cell transplant but only a small number of people who have severe thalassemia are able to find a good donor match and have the risky procedure. To prevent thalassemia would be very difficult since it is hereditary but it is advisable to visit a preconception genetic counselor for people that have thalassemia. 5 PHENYLKETONURIA Phenylketonuria (PKU) is a rare inherited disorder that causes an amino acid called phenylalanine to build up in the body. PKU is caused by a defect in the PAH gene (protein deletion) that helps create the enzyme, phenylalanine hydroxylase, needed to break down phenylalanine to tyrosine. Without this enzyme, a dangerous buildup can develop when a person with PKU eats foods that contain protein or eats aspartame, an artificial sweetener. This can eventually lead to serious health problems (Wikipedia, 2001). Both parents must pass on a defective version of the PAH gene for their child to inherit the disorder. This is called autosomal recessive. If one parent passes on an altered gene, the child won’t have any symptoms, but they will be a carrier of the gene. TYPES: The severity of PKU depends on the type (Phenylketonuria (PKU) - Symptoms and causes, 2018). They are: 1. Classic PKU: This is the most severe form of the disorder. Here the enzyme needed to convert phenylalanine is missing or severely reduced, resulting in high levels of phenylalanine and severe brain damage. 2. Less severe forms of PKU: In mild and moderate forms, the enzyme retains some function, so phenylalanine levels are not as high, resulting in a smaller risk of significant brain damage. They include variant PKU and non- PKU hyperphenylalaninemia. 3. Maternal PKU: Occurs in women who have PKU and become pregnant. Usually if they don’t follow the special PKU diet before and during pregnancy, blood phenylalanine levels become high and harm the fetus or cause a miscarriage. If peradventure they are able t give birth, there could be complications at birth including heart defects, facial abnormalities and low birth weight (Phenylketonuria: MedlinePlus genetics, 2021). SYMPTOMS: Newborns with PKU initially don’t have any symptoms until after few months without treatment (Slightham, 2017). The symptoms could either be mild or serious and they include: A musty odour in the breath, skin or urine caused by excess phenylalanine in the body. Neurological problems that may include seizures. Skin rashes (eczema). Fair skin and blue eyes, because phenylalanine can’t transform into melanin. Microcephaly – abnormally small head. Hyperactivity. Intellectual disability. Psychiatric disorders. TREATMENT OR MANAGEMENT: Adults or children with PKU can relieve their symptoms and prevent complications by following a special diet and taking medications. This special diet (should begin after birth and continue for the rest of life) limits food that contain phenylalanine like eggs, cheese, nuts, milk, beans, chicken, beef, pork, etc. They should also consume PKU formula which contains all the amino acids the body needs except for phenylalanine. At the same time, they need to work closely with a doctor or dietitian to maintain proper balance of nutrients and to keep a record of the amount of phenylalanine in the foods they eat. 6 NOTE: As PKU is a genetic condition, it can’t be treated. However, an enzyme assay can be done for people who plan on having children. This enzyme assay is a blood test that can determine whether someone carries the defective gene that causes PKU. 7 TAY-SACHS DISEASES TSD is a disease of the central nervous system passed from parents to child. It’s a neurodegenerative disorder that most commonly affects and is fatal in infants. It progressively destroys nerve cells in the brain and spinal cord. It is caused by a genetic mutation (protein deletion) in a gene that codes for an enzyme or protein called hexosaminidase A (Tay-Sachs disease, 2020). This enzyme helps break down fatty substances called gangliosides. In the absence of this enzyme, gangliosides build up to toxic levels in a child’s brain and affect the function of nerve cells. As the disease progresses, the child loses muscle control and it eventually leads to blindness, paralysis and death. It is an autosomal recessive disorder. TYPES AND SYMPTOMS: There are three types of TSDs and they and their symptoms include: 1. Infantile TSD: This occurs in infants and they usually develop normally for the first six months after birth. Thereafter neurons become distended with gangliosides causing a relentless deterioration of mental and physical abilities. Symptoms are deafness, progressive blindness, decreased muscle strength, increased startle response, paralysis, seizure, spasticity, slow growth and red spot on the macula (Tay-Sachs disease Symptoms and causes, 2018). Children usually die by 4 or 5 years. 2. Juvenile TSD: This is rarer than other forms of TSDs and it occurs in children between 2 – 10 years old. Symptoms include muscle weakness, seizures, and recurring respiratory infections. Children may live till 15 years old (Wikipedia, 2002). 3. Adult TSD: Also called chronic or onset TSD, it is the mildest form of Tay-Sachs. Symptoms appear during adolescence or adulthood and they include muscle weakness, slurred speech, unsteady gait, memory problems, and tremors. People with adult TSD may become full time wheel chair users. TREATMENT AND MANAGEMENT: There is no cure for TSD at present but palliative care could be administered (Herndon, 2021). This includes: 1. 2. 3. 4. 5. Medication for pain. Anti-epileptic medication to control seizures. Physical therapy. Nutritional support. Respiratory treatments to reduce mucus buildup in the lungs. To prevent this disease, screening or genetic testing should be done by parents to confirm that they are not carriers of the disease. 8 SICKLE CELL ANEMIA Sickle cell anemia is a genetic disease of the red blood cells. Red blood cells are shaped like discs, which gives them flexibility to travel through blood vessels but with sickle cell anemia, the red blood cells have an abnormal crescent shape resembling a sickle. This makes them sticky and rigid and they get trapped in small vessels thereby blocking blood and oxygen from reaching different parts of the body. It is an autosomal recessive condition therefore symptoms are only obvious if the parents both have the sickle cell trait. Sickle cell anemia is caused by a mutation in the gene that tells the body to make hemoglobin, an iron rich compound that makes blood red and helps carry oxygen from your lungs throughout the body. It results from the single amino acid substitution of valine for glutamic acid in the beta chain causing the production of faulty hemoglobin. The faulty hemoglobin is called hemoglobin S and it replaces normal hemoglobin which is called hemoglobin A. TYPES OF SICKLE CELL ANEMIA There are 4 main types and they are caused by different mutations in these genes (The Health Editorial Team, 2017). 1. Hemoglobin SS disease: The most common and severe type of sickle cell disease. It occurs when you inherit copies of the hemoglobin S gene from both parents. 2. Hemoglobin SC disease: Occurs when you inherit the Hb C gene from one parent and the Hb S gene from the other. Anemia is less severe than Hb SS. 3. Hemoglobin SB+ (beta) thalassemia: This affects beta globin gene production. The size of the red blood cell is reduced because less beta protein is made. Symptoms are not as severe. 4. Hemoglobin SB 0 (beta-zero) thalassemia: It also involves the beta globin gene and it’s similar to Hb SS anemia but symptoms are sometimes more severe. There are other types like Hemoglobin SD, Hemoglobin SE and Hemoglobin SO but they are very rare and have mild symptoms. Symptoms of Sickle cell anemia include (Sickle cell anemia - Symptoms and causes, 2020): 1. 2. 3. 4. 5. 6. 7. 8. 9. Periods of pain that could last for days. Blood clots. Swelling in hands and feet. Joint pain that resembles arthritis. Chronic neuropathic pain (nerve pain). Life-threatening infections. Anemia. Fussiness in babies. Jaundice. TREATMENT AND MANAGEMENT: There is no cure for sickle cell anemia (Sickle cell anemia: Symptoms, causes, treatments, 2019) but treatments include: 1. Rehydration with intravenous fluids and blood transfusions. 2. Immunizations and treating underlying infections. 3. Bone marrow transplant. 9 References Centers for Disease Control and Prevention. (2020, May 14). What is thalassemia? Retrieved from Centers for Disease Control and Prevention: https://www.cdc.gov/ncbddd/thalassemia/facts.html Herndon, J. (2021, January 6). Tay Sachs Disease: Treatments, symptoms, risks and more. Retrieved from Healthline: https://www.healthline.com/health/tay-sachs-disease Muncie, H. L., & Campbell, J. S. (2009, August 15). Alpha and beta thalassemia. Retrieved from AAFP American Academy Family Physicians: https://www.aafp.org/afp/2009/0815/p339.html National Heart, Lung, and Blood Institute. (2020). Thalassemias. Retrieved from NHLBI, NIH: https://www.nhlbi.nih.gov/health-topics/thalassemias Phenylketonuria (PKU) - Symptoms and causes. (2018, January 27). Retrieved from Mayo Clinic: https://www.mayoclinic.org/diseases-conditions/phenylketyonuria/symptoms-causes/syc-20376302 Phenylketonuria. (2001, April 30). Retrieved April 14, 2021, from Wikipedia: https://en.m.wikipedia.org/wiki/Phenylketonuria Phenylketonuria: MedlinePlus genetics. (2021). Retrieved from MedlinePlus - Health Information from the National Library of Medicine: https://medlineplus.gov/genetics/condition/phenylketonuria/ Sickle cell anemia - Symptoms and causes. (2020, January 30). Retrieved from Mayo Clinic: https://www.mayoclinic.org/diseases-conditions/sickle-cell-anemia/symptoms-causes/syc-20355876 Sickle cell anemia: Symptoms, causes, treatments. (2019). Retrieved from Cleveland Clinic: https://my.clevelandclinic.org/health/diseases/4579-sickle-cell-anemia Slightham, C. (2017, July 24). Phenylketonuria: Causes, symptoms, and diagnosis. Retrieved from Healthline: https://www.healthline.com/health/phenylketonuria Tay-Sachs disease - Symptoms and causes. (2018, May 16). Retrieved from Mayo Clinic: https://www.mayoclinic.org/diseases/symptoms-causes/syc-20378190 Tay-Sachs disease. (2002, June 13). Retrieved April 15, 2021, from Wikipedia: https://en.m.wikipedia.org/wiki/Tay%E2%80%93Sachs_disease Tay-Sachs disease. (2020). Retrieved from MedlinePlus - Health Information from the National Library of Medicine: https://medlineplus.gov/genetics/condition/tay-sachs-diseases/ Thalassemia: MedlinePlus medical encyclopedia. (2021). Retrieved from MedlinePlus - Health Information from the National Library of Medicine: https://medlineplus.gov/ency/article/000587.htm The Health Editorial Team. (2017). Sickle cell anemia: Types, symptoms, and treatment. Retrieved from Healthline: https://www.healthline.com/health/sickle-cell-anemia What kind of gene mutations are possible?: MedlinePlus genetics. (2021). Retrieved from MedlinePlus Medical Encyclopedia: https://medlineplus.gov/genetics/understanding/mutationsanddisorders/possiblemutations/ 10
