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Figure III. 1.4. Top: G-banded chromosome spread of a man with Down syndrome (47, XY, +21). The individual chromosome numbers are designated by convention. Bottom: ideogram of human chromosome 21 indicating the subregional localization of several genes of interest (see text). (From J. A. Fraser-Roberts and Marcus E. Pembrey 1978, with permission.)

Figure III. 1.4. Top: G-banded chromosome spread of a man with Down syndrome (47, XY, +21). The individual chromosome numbers are designated by convention. Bottom: ideogram of human chromosome 21 indicating the subregional localization of several genes of interest (see text). (From J. A. Fraser-Roberts and Marcus E. Pembrey 1978, with permission.)

synthase (CBS), which is implicated in the recessive metabolic disorder homocysteinuria (23620); the gene for liver-type phosphofructokinase (PFKL), which, in deficiency, leads to a type of hemolytic anemia (17186); and two oncogenes, ETS-2 (16474) and ERG (16508). The precise localization of ETS-2 to band 21q22 was a major indication that this region of chromosome 21 is the one responsible for many of the medical features of Down syndrome.

Individuals with Down syndrome have, in addition to classical facial features and mental retardation, a greatly increased risk of developing myeloid leukemia, a high incidence of cataract, and, in older patients, a neurological degeneration resembling Alzheimer's disease. The oncogene ETS-2 at 21q22 is known to be rearranged in acute myeloid leukemia

(McKusick 1986), and linked to this locus at 21q22 is the locus for the enzyme superoxide dismutase (SOD-1). Y. Groner and colleagues (1986) have reviewed molecular evidence that SOD-1 enhances lipid peroxidation, which leads to toxic neurological effects and to cataracts.

The Alzheimer's disease-like dementia of older Down syndrome patients suggested that the q22 region of chromosome 21 might be the location of the amyloid protein found in the senile plaques of Alzheimer's patients. D. Goldgaber and colleagues (1987) and R. E. Tanzi and colleagues (1987) independently reported that the amyloid-B protein gene mapped nearby at 21q21. The effect resulting from the extra copy of the amyloid-B protein gene in Down syndrome is an overproduction of amyloid and presenile plaque formation.

Finally, the advent of recombinant DNA techniques and sophisticated analytic tools for estimating genetic linkage relationships have enabled one group to focus on the cause of the trisomy. Using several well-mapped anonymous DNA sequences from chromosome 21 as well as a probe for SOD-1, A. C. Warren and colleagues (1987) have demonstrated that recombination among DNA markers on chromosomes 21 that have undergone nondisjunction, the event leading to a trisomy, occurs to a significantly lesser extent than it does in controls. Reduced recombination is indicative of asynapsis, or a failure of normal chromosome pairing. This result will very likely lead to the discovery of the molecular mechanism of chromosome pairing.

A Failure of Expectations: Kuril In August 1953, an officer in an Australian government patrol working in the South Fore region of the highlands of Papua New Guinea noted a peculiar condition:

Nearing one of the dwellings [at Amusi], I observed a small girl sitting down beside a fire. She was shivering violently and her head was jerking spasmodically from side to side. I was told that she was a victim of sorcery and would continue thus, shivering and unable to eat, until death claimed her within a few weeks. (J. McArthur 1953, in Lindenbaum 1979)

The condition from which she was suffering was locally called kuru (trembling or fear), a progressive neurological disorder peculiar to that region of Papua New Guinea.

Because the South Fore region was relatively isolated and the villages interrelated through extensive kinship ties, it was thought that kuru was a genetic disease occurring in an isolated district where inbreeding was elevated. However, kuru required that the gene be dominant in women and recessive in men for the epidemiology of the illness to be accounted for by a genetic factor (Bennett, Rhodes, and Robson 1959). Thus, even as early as 1963 the genetic etiology that seemed plausible was being discarded (Lindenbaum 1979).

The case of kuru is mentioned here briefly because it is a good example of the sophistication achieved in medical genetics and the study of human diseases. In the early part of the twentieth century, the power of the Mendelian model was so great that the abandonment of an unwieldy genetic hypothesis, which for kuru took only a couple of years, might have required decades. The true cause of kuru was a bizarre infectious agent that S. B. Prusiner (1982) termed a prion, or proteinaceous infectious particle. In an odd twist, the infectious component in prions, a relatively small protein called the prion protein, PrP 27-30 (Prusiner et al. 1984), was found to have a normal homolog in mammalian genomes, including human ones. PrP produced its effect by forming rodlike structures resembling amyloid, and it was thought that not only was the PrP gene to be found on chromosome 21 but that Alzheimer's disease and even Down syndrome might be associated with prion infection (Prusiner 1982). However, Y.-C. J. Liao and colleagues (1986) and R. S. Sparkes and colleagues (1986) independently reported cloning the human PrP gene and mapping it to chromosome 20. The story of the prion and of the PrP gene is still unfolding, and although it is not technically a genetic disease, kuru and neurological disorders like it fit well within the multifactorial heuristic model that moved the study of genetic diseases from one of recording oddities to a complex, interdisciplinary enterprise making use of a full range of techniques and technologies.

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