A computer simulating the sinister connection between Huntington'sdisease (HD) and nucleotide triplet expansion (junk DNA) predictedthat HD can only increase and spread among human populations.A study comparing the triplet repeats in HD and myotonic dystrophy(MD) plus five other far rarer neurogenetic maladies, concluded thatseverity of disease worsened with the number of repeats.And molecular analysis of an extended family over five generations,with HD-like symptoms and DNA triplets, found that this kindredalmost alone in the world shared its unique variant with sufferers inJapan, where the singular syndrome is widespread.All of the above came to light in three papers published between Fridayand Monday, in Science and Nature Genetics, all inculpatingnucleotide triplet repeats.Circa 1840, a family of freed slaves settled along the Haw River inrural North Carolina. From that day to this, many of its members overfive generations have come down with an autosomal dominantneurodegenerative disease, marked by ataxia (staggering gait), chorea(involuntary twitching), seizures, dementia, mental retardation andschizophrenia.Brain biopsies revealed loss of neurons in the dentate nucleus of thecerebellum, and other cerebellar damage. Technically, the disorder isrelated to DRPLA _ short for dentatorubropallidoluysian atrophy _but neurologists who study and care for the strange disease haveofficially named it "Haw River Syndrome" (HRS).DRPLA has been recently linked to the terminal region of chromosome12's short arm, and to pathologic expansion of the CAG triplet(cytosine-adenine-guanine) repeat. So at Duke University in Durham,N.C., neuro-geneticist Jeffrey Vance and his colleagues set out to see ifthe same triplet could explain HRS.Their report in the August issue of Nature Genetics, out yesterday istitled: "The Haw River Syndrome: Dentatorubropallidoluysian Atrophyin an African-American Family."In normal African-American controls, the paper noted, CAG repeatsitself from three to 13 times. This same range is found in the populationof Japan. The Duke team examined 24 Haw River family members,and in six affected individuals found that the number of tripletsrepeated 63 to 68 times.HRS symptoms usually set in between 15 and 30 years of age, withdeath following 15 to 25 years later.Vance told BioWorld Today that the symptomology of HRS is similarto that of HD "despite being caused by a different gene." That HRSgene carries the same CAG triplet repeats as HD, he noted, but onchromsome 12 instead of HD's chromosome 4.The Duke group and colleagues in Japan are now "looking at why it'sso common in Japanese and not in other populations."How Triplets Do Their DamageIf triplet repeats wreaked their havoc only on diseases as rare as HD,DRPLA and HRS, that would be bad enough. But the deadly DNAconfiguration is also responsible for the commonest genetic cause ofmental retardation in males, and the commonest form of musculardystrophy _ fragile X syndrome and myotonic dystrophy respectively.Microbiologist and electron microscopist Jack Griffiths and hisassociates at the University of North Carolina in Chapel Hill examinedan MD protein kinase gene containing an expanded CTG triplet repeatstretch. They could detect no messenger RNA; the gene was notexpressing.Griffiths is principal author of Science for July 29, out last Friday. Hisreport bears the title, "Preferential Nucleosome Assembly at DNATriplet Repeats From the Myotonic Dystrophy Gene."He and his co-authors surmised that this repression of transcriptionmight be explained by the abnormal number of repeats in MD formingnucleosomes _ proteins that are the basic structural units ofchromosomes. These allow or, in excess prevent, DNA replication. Invitro testing confirmed that "nucleosome assembly was found to betwo- to five-fold more likely over the triplet blocks than over theadjacent flanking [gene] regions."This phenomenon, Griffiths said, "needs to be studied in vivo."Normal, healthy humans carry a modest number of the same tripletrepeats that in higher amounts cause HD, MD, DRPLA and a handfulof even rarer, equally distressing, neurological syndromes. Monkeysand primates, Homo sapiens' evolutionary precursors, weigh in with amuch smaller population of the same junk DNA.Does this suggest that HD, the best-researched entity so far, is on therise? At Addenbrooks Hospital, affiliated with Cambridge University inEngland, genetic pathologist David Rubinzstein and his co-workers putthis question to the test _ in fact, to multiple testing.The results, of which Rubinzstein is first author, appear in the AugustNature Genetics, titled: "Mutational bias provides a model for theevolution of Huntington's disease and predicts a general increase indisease prevalence."FIrst, to set up a baseline of where health ends and HD begins, theresearchers determined precise CAG (HD gene) repeat numbers in fiveethnic groups, Saharan Blacks, South African Blacks, Asians, Japaneseand their own local East Anglians.These populations varied widely in their complement of CAG triplets,which most frequently ranged from a modal 15 to 17. But, asRubinzstein told BioWorld Today, these ethnic groups exhibited askewed distribution of triplet repeats. "More chromosomes had greaternumbers of them than the mode than had fewer than the mode."Next, monkeys, chimpanzees, gorillas and orangutans checked out withCAG modes closer to 9 per gene, and not more than 13. "This,"Rubinzstein observed, "implied an ancestral expansion in a primateancestor to the present-day situation."The skewed distribution in humans suggested to the researchers "that amutational bias that favored expansions, rather than contractions, couldmaybe account for this upward trend."So they set up a computer modeling experiment, putting in the primateswith their 9-to-13 repeats, added a mutational bias and otherlogarithmic factors, and "found it could reproduce the modern-dayhuman distributions quite closely."Their conclusion: "If our model is right, and if expansion doescontinue, we would predict _ in an evolutionary time scale, I think it'simportant to stress _ an increased incidence of Huntington's disease."That's the bad news. The good news is: "We're talking many centuriesat a minimum." n
-- David N. Leff Science Editor
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