Case study-Hemochromatosis

Case details

A 53-year-old man sees his family physician with concerns that his skin is “bronzing”- Figure

bronze diabetes

Figure- Bronze skin and diabetes, a sign of hemochromatosis

He is found to have diabetes as well as an elevated ferritin (a sign of iron over load).The physician suspects hemochromatosis and finds the patient carries a mutation where tyrosine is substituted  for cysteine at position 282(C282Y) of the HFE gene. The patient is diagnosed with hemochromatosis, which is a disease that results from which type of mutation?

A. Silent

B. Missense

C. Nonsense

D. Frameshift

E. Deletion

Answer- The correct answer is B- Missense mutation. Missense mutation is a type of point mutation where a single nucleotide change leads to incorporation of a different amino acid resulting in change in the functional capacity of the gene product.

Hemochromatosis is an autosomal recessive genetic disorder characterized by iron overload. Persons homozygous for mutations of the hemochromatosis gene, HFE, absorb three to four mg of dietary iron daily, a rate two to three times greater than normal. Normal storage sites become overloaded with iron, resulting in ferritin levels as much as ten times normal. With no mechanism to dispose of the excess, iron is deposited in the parenchymal cells of the liver, pancreas, pituitary, heart, synovium, and other tissues.

The hemochromatosis gene is located on the long arm of chromosome 6 where it codes for a membrane protein, HFE, which is 343 amino acids in size. The exact mechanism of the role of HFE in iron metabolism is not completely understood. A popular hypothesis is that HFE, along with a second protein, beta-2 microglobulin (beta-2M), interacts with TfR(Transferrin receptor) present on cell membranes. This interaction represses the affinity of TfR for the receptor, thus lowering the uptake of Tf into the cell. TfR have been found on the surface of a variety of cells, with the greatest concentration on the basolateral membrane of the intestine, hepatocytes, and erythrocyte precursors.

In HH (hereditary hemochromatosis) two mutations of the HFE gene have been described, C282Y and H63D. In the more prevalent C282Y mutation, there is a base substitution leading to a change in the amino acid in position 282 from cysteine (C) to tyrosine (Y). The loss of the sulfhydryl-containing amino acid disrupts the tertiary structure of HFE so that it no longer binds to beta-2 M. beta-2M appears to act along with other proteins to chaperone the newly synthesized HFE out of the Golgi and to the cell surface where it can then bind to TfR. In the C282Y mutation, HFE remains in the Golgi, never making it to the cell surface. The result is that Tf binding to TfR is enhanced and excessive amounts of iron are absorbed in the small intestine, hepatocytes, and other tissues.

As regards other options-

  • Silent mutation is also a type of point mutation leading to change in a single nucleotide, but due to redundancy (degeneracy) of the genetic code, same amino acid is incorporated, there is no change in the functional capacity of the gene product. Such a type of mutation remains unnoticed.
  • In non sense mutations, another example of point mutations, single nucleotide change leads to either change of a coding codon to termination codon with the resultant premature termination of the protein product, or the termination codon is changed to coding codon with the formation of a” run on peptide”.
  • In frame shift mutations, the reading frame is altered distal to the insertion or deletion of the nucleotides, the resultant protein is a garbled non functional protein.
  • Deletion type of mutations cause change in the reading frame.

Since in the given case, there is an incorporation of a single different amino acid, and an altered protein product, it is due to miss sense mutation.


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