Mice heterozygous at Aprt (adenine phosphoribosyltransferase) were used as a model to study in vivo loss of heterozygosity (LOH) in normal fibroblasts. Somatic cell variants that exhibited functional loss of the wild-type Aprt in vivo were recovered as APRT-deficient cell colonies after culturing in selection medium containing 2,6-diaminopurine (DAP), an adenine analog that is toxic only to cells with APRT enzyme activity. DAP-resistant (DAP r ) fibroblast variants were recovered at a median frequency of 12 ؋ 10 ؊5 from individual ears from progeny of crosses between mouse strains 129͞Sv and C3H͞HeJ. The frequency of DAP r variants varied greatly among individual ears, suggesting that they preexisted in vivo and arose at various times during development. Polymorphic molecular markers and a cytological marker on the centromere of chromosome 8 made it possible to discriminate between each of six possible mechanistic pathways of LOH. The majority (about 80%) of the DAP r variants were a consequence of mitotic recombination. The prevalence of mitotic recombination in regions proximal to Aprt did not correlate with meiotic map distances. In particular, there was a higher than expected frequency of crossovers within the interval 59 cM to 67 cM. The high spontaneous frequency of Aprt LOH, mediated primarily by mitotic recombination, is fully consistent with our previous results with human peripheral T cells from individuals known to be heterozygous at APRT. Thus, this Aprt heterozygote mouse is a valid model for studying somatic mutagenesis and mitotic recombination in vivo.Retinoblastoma is a prototype disease for understanding how loss of function of tumor suppressor genes (TSGs) leads to tumor formation. The so-called two-hit (two-mutational events) model explains elegantly the inheritance of genetic predisposition and development of retinal tumors (1). In familial cases, a preexisting RB1 germ-line mutation (the first hit) is inherited, predisposing the retinoblast cells to tumor development by requiring only a second mutational event (the second hit). In sporadic cases, somatic cells lack the predisposing mutation, and a retinoblast cell must acquire two separate RB1 mutations to progress to a tumor. In the two-hit model, the first hit, a rate-limiting step, renders a cell heterozygous or hemizygous at RB1. The second hit, which is frequently referred to as loss of heterozygosity (LOH), leads to the expression of the RB1 mutant phenotype (2). Because

A significant interaction among total serum cholesterol (TC), APOE genotype, and AD risk was found in a population-based study of elderly African Americans. Increasing TC was associated with increased AD risk in the group with no epsilon4 alleles, whereas TC was not associated with increased AD risk in the group with one or more epsilon4 alleles. Further study of the relationship between cholesterol and APOE genotype is needed to confirm this association, but the results suggest that cholesterol may be a potentially modifiable environmental risk factor for AD.

As part of a community-based study of Alzheimer's Disease (AD) in a Nigerian population aged 65 years and over, we have determined apolipoprotein E (APOE) genotypes on 56 subjects (39 controls and 17 subjects with dementia, including 12 with AD). The epsilon 4 allele of APOE was not associated with AD or dementia in this community-based sample. The epsilon 4 allele frequency was 17.6% in demented patients and 16.7% in AD patients compared with 20.5% in the control subjects. These findings are in marked contrast to the strong association between the epsilon 4 allele and AD in our previously reported study with African Americans.

Adenine phosphoribosyltransferase (APRT) deficiency in humans is an autosomal recessive syndrome characterized by the urinary excretion of adenine and the highly insoluble compound 2,8-dihydroxyadenine (DHA) that can produce kidney stones or renal failure. Targeted homologous recombination in embryonic stem cells was used to produce mice that lack APRT. Mice homozygous for a null Aprt allele excrete adenine and DHA crystals in the urine. Renal histopathology showed extensive tubular dilation, inflammation, necrosis, and fibrosis that varied in severity between different mouse backgrounds. Thus, biochemical and histological changes in these mice mimic the human disease and provide a suitable model of human hereditary nephrolithiasis.Adenine phosphoribosyltransferase (APRT; EC 2.4.2.7) is a ubiquitously expressed enzyme that catalyzes the synthesis of adenosine monophosphate from adenine and 5-phosphoribosyl-1-pyrophosphate (1). Adenine is produced endogenously as a by-product of the polyamine pathway and by the reaction of adenosine with S-adenosylhomocysteine hydrolase (2, 3). In the absence of functional APRT, adenine is oxidized by xanthine dehydrogenase (XDH; EC 1.2.3.2), by an 8-hydroxy intermediate, to 2,8-dihydroxyadenine (DHA) (4). The sparingly soluble nature of DHA at the normal pH of human urine (5) results in the excretion of DHA crystals in the urine and, frequently, the deposition of DHA stones in the kidneys. Adenine, which is not normally found in the urine at detectable levels, is also excreted.Clinical symptoms of APRT deficiency vary from benign to life-threatening and may be present from birth or have onset late in life (reviewed in ref.