Friedreich's Ataxia - Genetics

Genetics

Friedreich’s ataxia is an autosomal recessive disorder that occurs when a nuclear gene of an intronic GAA repeat codes for the protein frataxin. This mutation causes frataxin in the tissue to be reduced. Frataxin is an iron binding protein responsible for forming iron-sulphur clusters. One result of frataxin deficiency is mitochondrial iron overload which can cause damage to many proteins. The exact role of frataxin in normal physiology remains unclear.

The mutant gene contains expanded GAA triplet repeats in the first intron; in a few pedigrees, point mutations have been detected. Because the defect is located on an intron (which is removed from the mRNA transcript between transcription and translation), this mutation does not result in the production of abnormal frataxin proteins. Instead, the mutation causes gene silencing (i.e., the mutation decreases the transcription of the gene) through induction of a heterochromatin structure in a manner similar to position-effect variegation.

Besides expression of frataxin, long tracts of GAA repeats induce chromosome breaks in in vivo yeast studies.