Mendel and beyond 14/10/22 Flashcards
What is allelic heterogeneity?
This is when different mutations the same allele at the same locus produce the same disease.
What is locus heterogeneity?
This is a mutation in a different gene (loci) produce the same disease.
What does heterozygous mean?
Having two different alleles of a particular gene or genes.
What does homozygous mean?
Having two identical alleles of a particular gene or genes.
What is sickle cell anaemia and its symptoms?
Sickle cell is a disorder that affects haemoglobin. This causes RBC that are crescent shaped, inflexible and tend to stick to the vascular endothelium (the innermost lining of blood vessels).
This results in vascular obstruction that produces localized hypoxemia (lack of oxygen), painful sickling crises, and infarctions of various tissues, including bone, spleen, kidneys, brain, and lungs (an infarction is tissue death due to hypoxemia). Premature destruction of the sickled erythrocytes decreases the number of circulating erythrocytes and the haemoglobin level, producing anaemia. The spleen becomes
enlarged (splenomegaly), but infarctions eventually destroy this organ, producing some loss of immune function. This contributes to the recurrent and sometimes fatal bacterial infections (especially pneumonia) that are commonly seen in persons with sickle cell disease. About 10% of persons with sickle cell disease experiences a stroke before age 20 years. In North America, it is estimated that the life expectancy of persons with sickle cell disease are reduced by about 30 years.
How common is sickle cell?
Sickle cell disease affects millions of people worldwide. It is most common among people whose ancestors come from Africa; Mediterranean countries such as Greece, Turkey, and Italy; the Arabian Peninsula; India; and Spanish-speaking regions in South America, Central America, and parts of the Caribbean.
Is sickle cell a loss or gain of function?
This is a loss of function disorder.
What is the inheritance of sickle cell?
This is autosomal recessive.
What genetics cause sickle cell?
Sickle cell disease is typically caused by a single missense mutation (GAG to GTG) in the HBB gene that results in a substitution of valine for glutamic acid at position 6 of the β-globin polypeptide chain. This particular mutation accounts for 60-70% of sickle cell in the US.
What causes sickle cell?
In normal RBCs there are two subunits of alpha globulin produced by HBA gene and two subunits of beta globulin produced by HBB gene. Each of these subunits attach an iron containing molecule called heme which can attach an oxygen molecule.
In sickle cell the mutation in the HBB gene results in an amino acid substitution of valine for glutamic acid which alters the structure of the beta globulin known as haemoglobin S (HbS). Some other mutations in HBB can result in HbC and HbE.
This causes the haemoglobin molecules to aggregate, causing erythrocytes to assume a characteristic sickle shape under conditions of low oxygen tension, inflexibility, insolubility and stickier. This reason for these issues is because the amino acids that are switched have very different properties. Valine is bigger, polar, hydrophilic, and negatively charged, whereas glutamic acid is smaller, aliphatic, hydrophobic, and neutrally charged. This change scores 121 on Grantham’s score which is moderately radical and means that the change is not highly conserved.
What environmental factors can suddenly cause a sickle cell crisis?
Crisis can happen when there is a sudden change in temperature, very strenuous or excessive exercise, dehydration, infections, stress, high altitudes, alcohol, smoking, pregnancy, and other medical conditions such as diabetes.
Why is sickle cell beneficial?
It can protect against malaria.
What are the other types of sickle cell?
Hb Hyde park
Hb Kempsey
Hb hammersmith
B-thalassemia
a-thalassemia
What is Hb Hyde park?
Hb Hyde Park is a rare type of hereditary autosomal dominant mutation of CAC>TAC on codon 92 of beta globin HBB gene resulting in the replacement of histidine by tyrosine amino acid. This variant Hb has a tendency to form methaemoglobin (metHb). The iron ion in metHb is oxidized to ferric (Fe3+) which is unable to carry oxygen and the patients manifest as cyanosis. he ferric iron (Fe3+) in metHb is unable to carry oxygen or carbon dioxide. The oxygen affinity increases for the remaining ferrous (Fe2+) heme groups, so they bind to oxygen strongly and thus not ready to release oxygen to tissues. Patients are usually presented with cyanosis and the severity of the symptoms are proportional to the metHb level.
What is Hb Kempsey?
Hb Kempsey is a type of hereditary autosomal dominant mutation of the beta globulin HBB gene where there is a change of amino acid from aspartic acid to asparagine at point 99 on the gene. This causes the Hb to keep its high affinity structure so less oxygen is available to tissue.
This causes polycythaemia (high level of RBCs in blood) in heterozygotes and is lethal in people who are homozygotes for asparagine. This is a gain of function mutation.
What is the difference between B-thalassemia and a-thalassemia?
Thalassemia can be divided into two major groups, α-thalassemia and β-thalassemia. Depending on the globin chain that is reduced in quantity and unable to participate in normal tetramer formation the excess globulin will form molecules consisting of four chains of itself. These are termed homotetramers, in contrast to the heterotetramers normally formed by α and β chains.
In α-thalassemia, the α-globin chains are deficient, so the β chains (or γ chains in the foetus) are found in excess. They form homotetramers that have a greatly reduced oxygen-binding capacity, producing
hypoxemia.
In β-thalassemia, the excess α chains form homotetramers that precipitate and damage the cell membranes of red blood cell precursors. This leads to premature erythrocyte destruction and
anaemia.
How common is thalassemia?
Thalassemia was first described in populations living near the Mediterranean Sea, although it is also common in portions of Africa, the Mideast, India, and Southeast Asia.
What is B-thalassemia?
β-thalassemia minor - β-globin mutation in one copy of chromosome 11. A condition that involves little or no anaemia and does not ordinarily require clinical management.
β-intermedia and β-major - β-globin mutation where both copies of the chromosome carry a β-globin mutation. β-intermedia is less severe.
In intermedia and major β-Globin may be completely absent (β0-thalassemia), or it may be reduced to about 10% to 30% of the normal amount (β+-thalassemia). Typically, β0-thalassemia produces a more severe disease phenotype, but because disease features are caused by an excess of α-globin chains, patients with β0-thalassemia are less severely affected when they also have α-globin mutations that reduce the quantity of α-globin chains.
B-globulin is not produced until 2-6 months after birth, so symptoms don’t develop until then. Symptoms are anaemia which causes bone marrow expansion, which in turn produces skeletal changes, including a protuberant upper jaw and cheekbones and thinning of the long bones, splenomegaly, and infections are common.
Mutations are normally SNPs.
