We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.

The natural history and pathogenic potential of the recently identified TT virus (TTV) are currently a matter of intensive investigation. In an attempt to shed some light on these issues, nasal and blood specimens of 1-to 24-month-old children hospitalized with a clinical diagnosis of acute respiratory disease (ARD) were examined for the presence, load, and genetic characteristics of TTV. The results have indicated that at least in young children, the respiratory tract not only represents a route by which abundant TTV can be shed into the environment but also may be a site of primary infection and continual replication. Although we found no compelling evidence that TTV was the direct cause of ARD in some of the children studied, the average loads of TTV were considerably higher in patients with bronchopneumonia (BP) than in those with milder ARD, raising interesting questions about the pathophysiological significance of TTV at this site. Furthermore, group 4 TTV was detected almost exclusively in children with BP.TT virus (TTV)-a small, nonenveloped virus with a singlestranded, negative-polarity, circular DNA genome of 3.8 kbwas initially thought to be a circovirus similar to chicken anemia virus, porcine circovirus, and other viruses of animals, but it is now under consideration as the possible type species of an independent virus family (17,18,34,35). The taxonomy of the vast array of related viral agents that have been identified in humans since the first description of TTV by Nishizawa et al. in 1997 (21) is also uncertain. Recently, however, Okamoto and Mayumi (22) have divided TTV isolates into at least four phylogenetic clusters differing by over 40% at the nucleotide level: group 1 has the original TTV isolate as the prototype and includes genotypes 1 to 6; group 2 has PMV as the prototype and comprises genotypes 7, 8, 17, 22, and 23; group 3 has SANBAN and SENV as representative isolates and includes genotypes 9 to 16 and 18 to 20; and group 4 has YONBAN as the prototype and includes genotype 21. Furthermore, while the present report was in preparation, the same group identified several novel genotypes within group 4 TTV as well as members of a proposed fifth group (26). Additional related viruses are more dissimilar due to their smaller genome (2.8 kb) and are presently designated TTV-like minivirus or TLMV (6,33,34).The natural history and pathogenic potential of TTV are currently the subject of active investigation. From the epidemiological standpoint, evidence has accumulated that TTV viremia is extremely common in the general population worldwide, starting from early childhood (1,5,10,26,27), implying the existence of a very efficient means of transmission, and the observation that infectious TTV is shed in the feces has led to the suggestion that the fecal-oral route is the most likely one (36). With regard to the life cycle in infected hosts, both selflimited and persistent systemic TTV infections have been described (reviewed in reference 5) and chronic TTV viremia has been shown to result fro...

TT virus (TTV) is a recently identified widespread DNA virus of humans that produces persistent viremia in the absence of overt clinical manifestations. In an attempt to shed light on the dynamics of chronic infection, we measured the levels of TTV in the plasma of 25 persistently infected patients during the first 3 months of alpha interferon (IFN-␣) treatment for concomitant hepatitis C virus (HCV) infection. The first significant decline of TTV loads was observed at day 3 versus day 1 for HCV. Subsequently, the loads of TTV became progressively lower in most patients, but some initial responders relapsed before the end of the follow-up, suggesting that at least in some subjects the effects of IFN on TTV can be very short-lived. No correlation between the responses of TTV and HCV to therapy was found. Fitting the viremia data obtained during the first week of treatment into previously developed mathematical models showed that TTV sustains very active chronic infections, with over 90% of the virions in plasma cleared and replenished daily and a minimum of approximately 3.8 ؋ 10 10 virions generated per day. Low levels of TTV were occasionally detected in the peripheral blood mononuclear cells of patients who had cleared plasma viremia, thus corroborating previous results showing that these cells may support TTV replication and/or persistence.

A case-control study was carried out to determine whether residential exposure to environmental pollutants increased risk for canine lymphoma in pet dogs. One hundred one cases with cytologically or histologically confirmed lymphoma diagnosed at a veterinary teaching hospital between the middle of 1996 and the middle of 1998 were examined. Controls were obtained by choosing twice the number of dogs without neoplastic disease, with overlapping distributions of province of residence, age, sex, and breed. Information regarding animal management, residence type, professional or hobby use of chemicals by owners, and treatment with herbicides or other pesticides in the area frequently visited by the dogs was obtained with a multiple-choice questionnaire by telephone interview. Two variables were positively and independently associated with the disease, namely residency in industrial areas (odds ratio [OR]; = 8.5; 95% confidence interval [CI], 2.3-30.9) and use of chemicals by owners, specifically paints or solvents (OR = 4.6; 95% CI, 1.7-12.6). A significantly lower value of the mean age of disease onset was found in the group of dogs at risk in comparison with the group of all other dogs (6.1 +/- 0.4 years, n = 36 versus 7.5 +/- 0.4 years, n = 65, respectively; P = .008). Variables describing animal care and pesticide use were either not associated with the disease or were uninformative. We suggest that canine lymphoma may be considered a sentinel of potentially hazardous situations for humans, because of the relatively short latency between exposure and disease onset.

In 239 torquetenovirus-positive people, multiple-genogroup infections were common and associated with higher viral loads than would be expected from simple additive effects. The latter observation was restricted to the infections which included both genogroups 1 and 3, pointing to the possible existence of some kind of infection facilitation between these genogroups.Torquetenovirus (TTV), formerly known as TT virus, was discovered in 1997 by Japanese workers in the blood of a patient with cryptogenetic hepatitis and has since been shown to sustain long-term, possibly permanent viremia in a surprisingly high proportion (around 80%) of the general population worldwide (1-3, 5, 12, 13). It is also clearly documented that the loads of TTV (viral load [VL]) in plasma may differ extensively among individual hosts (15). Due to its high genetic heterogeneity, TTV is currently subdivided into five highly divergent genogroups, designated 1 to 5 (4, 14). Although multiple-genogroup TTV infections are quite frequent (1, 6, 7), there have been no reported studies on the possible relationships between the number of genogroups carried and the total VL present in an individual.In the course of our studies, we noted that individuals with high VLs tended to yield more TTV genogroups than those with low VLs. Thus, in preliminary work, we examined whether this might be due to the fact that high VLs permitted detection of TTV genogroups which escaped detection in low-VL plasma because they represented a small fraction of the total VL. The experiments did not support this explanation. In particular, the processing of five low-VL plasma specimens that had yielded one or two TTV genogroups in such a way as to augment 10-and 100-fold the amount of DNA examined in the typing assays had little or no impact on the number of genogroups detected. Similarly, when five specimens positive for four genogroups and with VLs between 6.1 and 6.8 log 10 copies per ml were diluted 100-fold, i.e., to a point where the VLs were in the range that is associated mostly with single-genogroup infections, they still yielded three to four TTV genogroups (data not shown).Such failure to provide an easy explanation for the observation prompted a systematic look at the issue. To this purpose, we assessed the presence, load, and genogroup(s) of TTV in plasma samples from 300 people. The methods have been previously reported (8, 9, 15). Briefly, extracted DNA was assayed for TTV presence and load with a universal TaqMan real-time PCR having the potential to detect and quantitate all hitherto-recognized genetic forms of the virus (8, 9). TTVpositive DNA extracts were then typed with five distinct genogroup-specific PCRs, as described previously (8, 9), using the primer sets shown in Table 1. TTV was detected in 267 people (89%) and successfully typed in 239. Most TTV-positives carried two distinct genogroups, followed by one, three, and four. TTV genogroups 1 and 3 were the most prevalent, followed at a distance by genogroups 4 and 5, while genogroup 2 was rather in...

TT virus (TTV) produces chronic plasma viremia in around 90% of healthy individuals of all ages and has, therefore, been proposed as a commensal human virus. We recently demonstrated that in children hospitalized for acute respiratory diseases high TTV loads were associated with severe forms of disease. Here, we report that in such children TTV loads showed an inverse correlation with the percentage of circulating total T and helper T cells and a direct correlation with the percentage of B cells. Thus, florid TTV replication might contribute to lymphocyte imbalances and, possibly, immunosuppressive effects, thus resembling related animal viruses.TT virus (TTV) has genome properties similar to those of animal circoviruses, such as chicken anemia virus and porcine circovirus. Because it produces chronic plasma viremia in around 90% of healthy individuals of all ages worldwide and no associated disease has yet been identified, it has been suggested that TTV might be totally apathogenic (for reviews, see references 1 and 11). Recently, we tested for the presence of TTV and assessed viral load by universal untranslated-region real-time PCR in 157 children under 2 years old with acute respiratory diseases (ARD) on the day of hospital admission and obtained convincing data that TTV might replicate in the respiratory tract (5). Also, although we found no evidence that TTV might be the direct cause of ARD, TTV loads in both nasal swabs and plasma samples were substantially higher in subjects with bronchopneumonia (BP) than in the subjects with milder ARD (laryngitis, bronchitis, and bronchiolitis), suggesting among other possibilities that TTV could be locally or systemically immunosuppressive and aggravate disease induced by other agents (5). However, there is no information on this matter except for recent reports showing an inverse relationship between TTV burdens and CD4 cell counts in patients with human immunodeficiency virus type 1 (2, 10, 13).In this study, we examined, with informed parental consent, peripheral leukocyte and lymphocyte subset counts in 40 randomly chosen children with ARD from the above study (5). Of the 40 children, 18 had an X-ray-confirmed diagnosis of BP. The same blood samples used for TTV assays were analyzed. Features similar to those described for the entire sample (5) were confirmed in this subset. In particular, mean TTV loads in plasma were significantly higher in BP patients than in children with milder ARD (7.9 Ϯ 1.2 versus 5.6 Ϯ 2.3 log 10 per ml [P Ͻ 0.001]). Interestingly, although all absolute cell counts were within the values reported for healthy children of similar age (3) with unknown TTV status (but presumably mostly TTV positive, based on what is currently known of TTV epidemiology [1,11]), the percentages of CD3 (total T lymphocytes) and CD4 cells (T helper lymphocytes) showed an inverse correlation with the levels of TTV. By contrast, the percentages of CD19 cells (B lymphocytes) showed a positive correlation with TTV levels (Fig. 1). On the other hand, lymphocyte and TT...

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Adenomatous polyposis coli (APC) is an autosomal dominant disease characterized by the development of hundreds of colorectal adenomatous polyps during the first decades of life. The expression of the disease varies, as the age of onset of colonic cancer and the severity of extracolonic manifestations often differ between affected families. An attenuated form of APC has also been described in which a small number of polyps and a later age of onset of colonic cancer is observed. Cloning of the APC gene has allowed disease-causing mutations in APC families to be identified. Here, we report a novel splice site mutation (a G to T transversion at position +5 of the splice donor site in intron 9) in the APC gene of affected individuals in an Italian family. Characterization of the transcription products from this mutant APC allele revealed that normal splicing was disrupted: a shorter mRNA was expressed in which exon 8 was connected directly to exon 10. This created a shift in the reading frame and the introduction of a stop codon at position 1358. In addition, some normal APC transcript was produced from the mutant allele in lymphoblastoid cells. A comparison of the clinical features of affected members of this family with four unrelated Italian APC kindreds, in which the same AAAAG deletion at position 3926 has been found, showed a significant difference in the onset of disease symptoms and in the age of death attributable to colorectal cancer. Inefficient exon skipping may be, at least in part, responsible for the delay in the development of the disease in the reported family.