The gene for Huntington's disease, discovered last March,"doesn't look like anything that's been discovered before,"Marcy MacDonald, assistant professor of neurology at theHarvard Medical, School told BioWorld. The mechanism ofmutation is also bizarre.
Her paper, with first author and colleague James Gusella andothers, was one of more than 150 reports that the AmericanMedical Association (AMA) released last week at a briefing onthe new importance of genetics and molecular biology inmedicine. The researchers reviewed the molecular genetics ofthe gene in the AMA publication, Archives of Neurology.
Huntington's affects about one in 10,000 Caucasians. Itsformerly mysterious non-Mendelian inheritance results fromits peculiar mechanism, which is common to several othergenes that were discovered this year.
The gene has a number of highly unstable repeated sequencesof CAG. "Their length changes almost every time they arepassed from parent to child," MacDonald told BioWorld. Thegene gains abnormal function as the number of repeatsincreases somewhere between 34 and 38.
Although the length can decrease as the gene is passed fromparent to child, on average, it increases .4 to nine units. Onemajor challenge, then, is to try to prevent the instability, saidMacDonald.
Furthermore, increasing numbers of repeats correlate inverselywith age of onset, which ranges from age 2 to well over 70.
Two other diseases, spinal bulbar muscular atrophy (SBMA)and spinal spino cerebellar ataxia type I (SSCA 1), are causedby similar numbers of CAG repeats. As in Huntington's, thegene for SSCA 1 is novel, but SBMA codes for an androgenreceptor.
(Fragile X syndrome and myotonic dystrophy are also causedby repeated triplet sequences, but the numbers are severalorders of magnitude greater than in Huntington's.)
The oddity of the sequence itself is matched by the mysteriouspattern of pathology. In an article published in this month'sissue of Nature Genetics, Theresa Strong, Francis Collins andothers described how mRNA from the gene is expressedthroughout the brain, while the damage is confined mostly tothe striatum.
This "suggests that HD is a gene important for the normalfunction of neurons," they wrote. Similar observations apply toSBMA and SCA 1.
The gene's dominance suggested to Strong and her colleguesthat expanded triplets do not inactivate the protein, but endowit with a new, additional function that somehow kills neuronsin the basal ganglia. "The (normal) mRNA and the protein arethere even when the Hd gene is mutant, so it isn't the lack ofprotein that's causing those cells to die," the researchers said.
"The delineation of the primary defect in HD has placed us atthe start of the long road to a complete understanding of thedisorder," Gusella and his colleagues concluded. "But it is a roadwhere each way station could be a clue to treatment."
-- David C. Holzman Washington Editor
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