Mutations have been found to cause disease through one of four different effects on protein function. They are:
- loss of function
- gain of function
- heterochronic expression
- ectopic expression
Gain of function mutation:
the acquisition of a novel property by the mutant protein
Heterochronic expression mutation:
the expression of a gene at the wrong time
Ectopic expression:
the expression of a gene in the wrong place
alpha-thalessemias are due to what type of mutation?
- loss of function due to deletion
- leads to a reduction in gene dosage
The severity of a disease that results from loss-of-function mutations can generally be correlated to the:
- amount of function lost
- retention of a small degree of residual function by the mutant protein greatly reduces the severity of the disease
hemoglobin Kempsey
locks hemoglobin in its high oxygen affinity state, thereby reducing oxygen delivery to tissues.
Beta-thalassemias are characterized by:
- a reduction in the abundance of beta-globin
- due to loss of function mutation
Sickle Cell Disease:
- due to an amino acid substitution that has no effect on the ability of sickle hemoglobin to transport oxygen.
- Rather, unlike normal hemoglobin, sickle hemoglobin chains aggregate when they are deoxygenated to form polymeric fibers that deform red blood cells.
Heterochronic and ectopic mutations
- alter the regulatory regions of a gene to cause its inappropriate expression, at an abnormal time or place.
Hereditary Persistence of Fetal Hemoglobin (HPFH):
- mutations in hemoglobin regulatory elements lead to the continued expression in the adult of the gamma-globin gene, which is normally expressed at high levels only in fetal life.
Globin switching:
- the change in the expression during development of the various globin genes
The hereditary disorders of hemoglobin can be divided into three broad groups. They are:
- Structural variants
- Thalessemias
- Hereditary persistence of fetal hemoglobin (HPFH)
Structural variants:
alter the globin polypeptide without affecting its rate of synthesis
Thalessemias:
- decreased synthesis (or, rarely, extreme instability) of one or more of the globin chains
- results in an imbalance in the relative amounts of the alpha and beta chains
Hereditary persistence of fetal hemoglobin (HPFH):
- impair the perinatal switch from gamma-globin to beta-globin synthesis
The hemoglobin structural variants can be separated into three classes. They are:
- hemolytic anemia
- altered oxygen transport
- thalessemias
Cinical features of Sickle Cell Disease:
- a tendency of the red blood cells to become grossly abnormal in shape (i.e., to sickle) under conditions of low oxygen tension
- hemolytic condition
Molecular pathology of Sickle Cell Disease (HbS):
- single change in the beta-globin gene
- (glu-6 to val)
Sickle Cell Anemia: how sickling occurs and its consequences.
- in deoxygenated blood, HbS is only 1/5 as soluble as normal hemoglobin
- mutation makes surface hydrophobic
- HbS aggregate in the form of rod-shaped polymers or fibers, which distort the erythrocyte to a sickle shape.
- mis-shapen erythrocytes are less deformable
- cannot squeeze in single file through capillaries, thereby blocking blood flow and causing local ischemia.
HbC is due to:
- a substitution at the 6th position of the beta-chain
- glu replaced by lys
- mutation at same position as HbS
Clinical features of HbC:
- less soluble than Hb A
- tends to crystallize in red blood cells, reducing their deformability in capillaries and causing a mild hemolytic disorder
beta-0 thalassemia
no HbA is present
beta+ thalassemia
some HbA present
