Quite a few neurological disorders [see table below] are turning out to have a bizarre genetic basis consisting of variations in a short region that is repeated a few to hundreds of times. If in a coding open reading frame (ORF), the repeat is translated; if in a leader or trailer sequence (untranslated reading frame, UTR) it is not. The disease condition is associated with increasingly long repeats. Disease onset can be earlier in subsequent generations if the repeat length has increased.
Recall that prion protein contains a repeat region, typically a highly conserved octapeptide repeated 5-6 times [e.g., PQGGGGWGQ PHGGGWGQ PHGGGWGQ PHGGGWGQ PHGGGWGQ PHGGGGWGQ]. Furthermore, there are numerous instances where increased length (from 1 to 9 additional repeats) leads to familial CJD. The function of this domain in prion protein is not understood, but it is worth exploring whether it has anything in common with (tri-nucleotide and longer) repeat neurological conditions.
McLaughlin et al describe the situation in Huntington Disease, a condition associated with a simple CAG tri-nucleotide repeat (giving poly-glutamine) that is innocuous at the level of 11-34 repeats but becomes a serious neurological disorder when 37-180 repeats in length. Three models are considered by way of explanation:
|Condition||Acronym||DNA Repeat||position||AA||normal repeats||disease repeats|
|Spinal-bulbar muscular atrophy||SBMA||CAG||ORF||gln||.||37-180|
|Spinoocerebellar ataxia 1||SCA1||CAG||ORF||gln||.||37-180|
|Machado- Joseph disease||MJD||CAG||ORF||gln||.||37-180|
|Fragile X syndrome||FRAXA||CGG||UTR||---||.||200-2000|
|Fragile X syndrome||FRAXE||CGG||UTR||---||.||200-2000|
|D4 dopamine receptor||D4DR||.||.||.||2-11||7|
(Other mRNAs which contain poly-CAG tracts include androgen receptor, TATA-binding protein, achaete scute homologue, pim-i proto oncogene, natruretic peptide, preproenkepahlin (8), and calmodulin-1.)