Characterized more than a century ago, Friedriech’s ataxia is a debilitating neurodegenerative disease, effecting gait (ability to walk), arm movement, and progressive muscular weakness. Symptoms usually are present before 25, but rarely begin before the onset of puberty.
The molecular mechanism was uncovered through familial studies in the 80s and a shared molecular event was identified in the 90s. A common mutation was identified, the change involved the expansion of a GAA nucleotide repeat in the first intron of the frataxin gene. Since the mutation is in an intron the individuals with this mutation can make the frataxin protein, but only at very reduced levels.
With lowered frataxin levels come abnormally high iron levels within neuronal mitochondria. These individuals have mitochondria that are drowning in iron while sometimes presenting in the clinic with iron deficiency by blood test.
From a toxicological point of view, a tough diagnosis.
Frataxin itself is not well understood. The protein is involved in iron storage and transport, but it does not appear to be a transporter. Under normal conditions there is little free iron in the mitochondria, but with reduced frataxin levels, mitochondrial function is severely compromised.
We have talked a bit in class about mutations that do occur within the coding region of genes and I have asked the toxicology students to describe how such a mutation as a repeat nucleotide expansion in an intron could lead to reduced protein levels. I have also asked them to suggest a genetic test for Friedriech’s ataxia, so if you want to know more, read on.
They will be using Schmucker and Puccio’s 2010 Human Molecular Genetics paper, “Understanding the molecular mechanisms of Friedreich’s ataxia to develop therapeutic approaches” to develop their responses.