Question

QUESTION 36 Ferritin is an intracellular protein that stores essential iron and releases it in a controlled fashion when needed. Hereditary hyperferritinaemia-cataract syndrome (HHCS) is a relatively rare disorder with an autosomal dominant trait. The disease is characterized by increased L-ferritin in serum and tissues and early onset of bilateral cataracts. Iron metabolism is normal, and there is no tissue iron overload. HHCS can be caused by mutations in the 5' non-coding region of the ferritin gene. Which of the following hypothesis are reasonable mechanisms that explain how a mutation in the 5' UTR of the ferritin gene could lead to overexpression of the ferritin protein. Mutations in the 5' end of the ferritin gene increases the rate of degradation of the ferritin mRNA. Mutations in the 5' UTR of the ferritin mRNA disrupt a key secondary structure that normally plays a role in regulating the cellular concentration of ferritin by mildly inhibiting the translation of the ferritin transcript. Mutations in the 5' end of the ferritin gene that lead to HHCS might be creating an alternative splice site that leads to a ferritin protein with the same amino terminus but different carboxy terminal. Mutations in the 5' end of the ferritin gene that lead to HHCS might be increasing the ribosome-recruiting efficiency of the transcript. Mutations in the 5' end of the ferritin gene that lead to HHCS might be improving the efficiency of post-translational modifications on the ferritin protein.

Answer 1

• Mutations in the 5' UTR of the ferritin mRNA disrupt a key secondary structure that normally plays a role in regulating the cellular concentration of ferritin by mildly inhibiting the translation of the ferritin transcript.
• Mutations in the 5' end of the ferritin gene that lead to HHCS might be increasing the ribosome-recruiting efficiency of the transcript.

Since the 5' UTR is not usually translated, instead used to regulate mRNA stability and expression, a mutation in the 5' UTR of Ferritin mRNA that increases the translation of Ferritin would most likely be involved in the loss of regulation of the mRNA. This can be either due to increased ribosome recruitment or de-regulation of translational repression.