Lecture 16 - Protein Mutations and Disease

Question 1

Thalassemias

Answer 1

• Thalassemias are due to reduced synthesis of either the α polypeptide chains (α-thalassemias) or β polypeptide chains (β -thalassemias) of hemoglobin.
• The result is anemia which may be severe.

Question 2

Sickle cell disease

Answer 2

• Most commonly, in the B subunit a Glu to Val mutation replaces a polar side-chain group on the outside surface of the molecule with a non-polar hydrophobic side chain. This is a non-conservative mutation.
• reduces the solubility of deoxyhemoglobin and allows formation of fibrous polymeric filaments of deoxyhemoglobin that precipitate in the red blood cells.
• This precipitation leads to an ultra-structural deformity
• Only individuals homozygous for HbS exhibit the disease
• Individuals heterozygous for HbS resist the malaria parasite, which spends a part of its life cycle in red blood cells
• Hydroxyurea has been introduced for the treatment of sickle cell anemia. By a mechanism not understood, hydroxyurea results in re-expression of the fetal hemoglobin gene which decreases HbS precipitation

Question 3

Glycated Hemoglobin (HbA1c)

Answer 3

• HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time
• It is formed in a non-enzymatic glycation pathway by hemoglobin’s exposure to plasma glucose

Question 4

p53 Tumor Suppressor Gene

Answer 4

• p53 is a DNA-binding protein that is present in low levels in normal cells but strongly elevated after DNA damage where it either promotes cell cycle arrest or apoptosis, largely through acting as a transcriptional regulator
• Major consequence of loss of p53 function is that cells with corrupted genomes continue to proliferate
• More than half of all human cancers show either an absence of p53 protein or mutations in the gene
• Individuals who inherit only one functional copy of the p53 gene are predisposed to cancer. This propensity is called the Li-Fraumeni syndrome; very rare, involves development of several independent tumors in a wide variety of tissues at an early age

Question 5

Cystic Fibrosis

Answer 5

• an autosomal recessive genetic disorder of the secretory processes of all exocrine glands that affects both mucus secreting and sweat glands throughout the body
• The primary physiological defect is disregulation of chloride ion transport.
• The clinical features of the disorder include recurrent pulmonary infections, pancreatic insufficiency, malnutrition, intestinal obstruction and male infertility
• results in loss or reduction of chloride secretion into the airways which causes increased sodium uptake into the cell and both these ion changes causes increased water reabsorption from the lumen. This lowers the water content of the mucus blanket leading to defective mucociliary action and accumulation of hyperconcentrated viscid secretions that obstruct the air passages and predispose to recurrent pulmonary infections
• Over 70% of the identified mutations in the CFTR gene result in a protein that is lacking a critical phenylalanine residue at position 508, termed DF508 (deleted Phe-508)
• For CFTR, the missing Phe-508 leads to a conformational change in the protein that prevents normal glycosylation and transport out of the ER. Ironically, if this mutant form of CFTR is expressed by itself and assayed in artificial systems, the protein will still function to some degree to translocate chloride ions.