Fatal familial insomnia
Fatal familial insomnia (FFI) autosomal dominant prion disease. Meaning it is a genetic disease that need only be inherited from one parent for it to be apparent, however it will not appear until later life. Prions are normal proteins usually found in the brain which have been mutated and are then damaging to cells, as when a prion gets into a cell containing normal proteins it converts the other proteins into prions. This process repeats and causes chains which in turn harms normal cellular functions. Depending on where this prion aggregation is occurring will determine the type of prion disease. In the case of FFI the prions cause sever atrophy in the anterior ventral and mediodorsal thalamic nuclei. Which in turn causes the clinical characteristics of inattention, sleep loss and dysautonomia.
Until 1992 the exact cause of this disease was not known until a group of 20 scientists, lead my Rossella Medori M.D. made the discovery that FFI is ‘a prion disease with a mutation at codon 178 of the prion protein gene’ and published an article of the same name in The New England Journal of Medicine.
Their methodology for this experiment included tissue samples, immunochemical evaluation for PrP (both dot blot procedures and western blot procedures’ , analyses of the PrP gene and Linkage analysis with the former two procedures proving most effective in finding the accurate cause.
The analyses of the PrP gene began with DNA being extracted from those effected and then amplified using primers. The procedure for the amplification consisted of 30 cycles with an automated thermal cycler, each cycle consisted of denaturation at 94°C, annealing at 65°C and extension at 72°C with each step lasting 1 minute. Sections of the amplified prion protein coding region was sub cloned so each allele of the gene could be sequenced. The amplified PrP double-strand DNA was then cleaved with restriction enzymes and the two largest fragments were ligated and then sequenced using a program.
This showed that on codon 178 a heterozygous mutation GAC-AAC had occurred resulting in asparagine being replaced by aspartic acid on the PrP gene.
After this process the Linkage analysis could occur using the MLINK program which tested the linkage between the fatal phenotype and the point mutation at codon 178 of the prion protein gene. It was found that in this mutation asparagine is substitutes for aspartic acid. Through testing various members of the family who either were definitely, probably or possibly affected by the disease, and members of the public who were definitely not affected this theory of mutation was proven.
One aspect that was yet to be understood was how the age and onset of this disease could differ between patients until in 1999 it was found that the mutation on codon 178 is coupled with methionine at position 129. When the codon 129 is a homozygote expressing methionine also in the non-mutated allele, the disease runs a shorter course. However when codon 129 expresses valine in the non-mutated allele, and so is a heterozygote the disease runs a much longer course.
This advance in our understanding of genetically caused prion diseases, in this case specifically FFI, is a key discovery as it will not only hopefully lead to a cure of this particular prion disease, but also many others. Such as Alzheimer’s and Parkinson’s disease which have been recently discovered to also be caused by prions. In conjunction with recent advances in genetic engineering it is possible that hereditary prion diseases such as FFI could be eradicated from society.
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Campbell, N 2009 Biology 8th ed. Australian Version, Pearsons Education Australia, Sydney p. 252, 395
Cortelli, P 1999 Fatal familial insomnia: clinical features and molecular genetics, Institute of Clinical Neurology, University of Bologna, Italy p. 23-29
Medori, R 1992 Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene, The New England Journal of Medicine, Massachusetts Medical Society, Massachusetts p. 444-449